Neil A Williams

Publications of Neil A Williams

• Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue.

  Authors: Jeffrey Pido-Lopez, William W Kwok, Timothy J Mitchell, Robert S Heyderman, Neil A Williams

  PLoS pathogens. 12/2011; 7(12):e1002396.

  The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) TThe upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines.

• Do multiple concurrent infections in African children cause irreversible immunological damage?

  Authors: Sarah J Glennie, Moffat Nyirenda, Neil A Williams, Robert S Heyderman

  Immunology. 10/2011; 135(2):125-32.

  Much of the developing world, particularly sub-Saharan Africa, has high levels of morbidity and mortality associated with infectious diseases. The greatest risk of invasive disease is in the young,Much of the developing world, particularly sub-Saharan Africa, has high levels of morbidity and mortality associated with infectious diseases. The greatest risk of invasive disease is in the young, the malnourished and HIV-infected individuals. In many regions in Africa these vulnerable groups and the wider general population are under constant immune pressure from a range of environmental factors, under-nutrition and multiple concurrent infections from birth through to adulthood. Intermittent microbial exposure during childhood is required for the generation of naturally acquired immunity capable of protection against a range of infectious diseases in adult life. However, in the context of a resource-poor setting, the heavy burden of malarial, diarrhoeal and respiratory infections in childhood may subvert or suppress immune responses rather than protect, resulting in sub-optimal immunity. This review will explore how poor maternal health, HIV exposure, socio-economic and seasonal factors conspire to weaken childhood immune defences to disease and discuss the hypothesis that recurrent infections may drive immune dysregulation, leading to relative immune senescence and premature immunological aging.

• Deteriorating pneumococcal-specific B-cell memory in minimally symptomatic African children with HIV infection.

  Authors: Oluwadamilola H Iwajomo, Adam Finn, Peter Moons, Rose Nkhata, Enoch Sepako, Abiodun D Ogunniyi, Neil A Williams, Robert S Heyderman

  The Journal of infectious diseases. 08/2011; 204(4):534-43.

  Invasive pneumococcal disease is a leading cause of human immunodeficiency virus (HIV)-associated mortality in sub-Saharan African children. Defective T-cell-mediated immunity partially explains thisInvasive pneumococcal disease is a leading cause of human immunodeficiency virus (HIV)-associated mortality in sub-Saharan African children. Defective T-cell-mediated immunity partially explains this high disease burden, but there is an increased risk of invasive pneumococcal disease even in the context of a relatively preserved percentage of CD4 cells. We hypothesized that impaired B-cell immunity to this pathogen further amplifies the immune defect. We report a shift in the B-cell compartment toward an apoptosis-prone phenotype evident early in HIV disease progression. We show that, although healthy HIV-uninfected and minimally symptomatic HIV-infected children have similar numbers of isotype-switched memory B cells, numbers of pneumococcal protein antigen-specific memory B cells were lower in HIV-infected than in HIV-uninfected children. Our data implicate defective naturally acquired B-cell pneumococcal immunity in invasive pneumococcal disease causation in HIV-infected children and highlight the need to study the functionality and duration of immune memory to novel pneumococcal protein vaccine candidates in order to optimize their effectiveness in this population.

• Impaired CD4 T cell memory response to Streptococcus pneumoniae precedes CD4 T cell depletion in HIV-infected Malawian adults.

  Authors: Sarah J Glennie, Enoch Sepako, David Mzinza, Visopo Harawa, David J C Miles, Kondwani C Jambo, Stephen B Gordon, Neil A Williams, Robert S Heyderman

  PloS one. 01/2011; 6(9):e25610.

  Invasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African adults. CD4 T cell depletion may partially explain this high disease burden but those withInvasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African adults. CD4 T cell depletion may partially explain this high disease burden but those with relatively preserved T cell numbers are still at increased risk of IPD. This study evaluated the extent of pneumococcal-specific T cell memory dysfunction in asymptomatic HIV infection early on in the evolution of the disease. Peripheral blood mononuclear cells were isolated from asymptomatic HIV-infected and HIV-uninfected Malawian adults and stained to characterize the underlying degree of CD4 T cell immune activation, senescence and regulation. Pneumococcal-specific T cell proliferation, IFN-γ, IL-17 production and CD154 expression was assessed using flow cytometry and ELISpot. We find that in asymptomatic HIV-infected Malawian adults, there is considerable immune disruption with an increase in activated and senescent CD4+CD38+PD-1+ and CD4+CD25(high)Foxp3+ Treg cells. In the context of high pneumococcal exposure and therefore immune stimulation, show a failure in pneumococcal-specific memory T cell proliferation, skewing of T cell cytokine production with preservation of interleukin-17 but decreased interferon-gamma responses, and failure of activated T cells to express the co-stimulatory molecule CD154. Asymptomatic HIV-infected Malawian adults show early signs of pneumococcal- specific immune dysregulation with a shift in the balance of CD4 memory, T helper 17 cells and Treg. Together these data offer a mechanistic understanding of how antigen-specific T cell dysfunction occurs prior to T cell depletion and may explain the early susceptibility to IPD in those with relatively preserved CD4 T cell numbers.

• Mucosal immunity in resource-limited setting: is the battle ground different?

  Authors: Sarah J Glennie, Neil A Williams, Robert S Heyderman

  Trends in microbiology. 11/2010; 18(11):487-93.

  In many developing countries, populations are under considerable pressure from high bacterial exposure on mucosal surfaces. Immune dysregulation in this setting is multifactorial and is driven by aIn many developing countries, populations are under considerable pressure from high bacterial exposure on mucosal surfaces. Immune dysregulation in this setting is multifactorial and is driven by a range of environmental factors, undernutrition and coinfections such as measles, malaria and HIV. Disruption or subversion of respiratory-tract and intestinal epithelial barriers leads to increased invasion by mucosal pathogens and a high frequency of life-threatening bacterial disease. It is our opinion that a process of epithelial barrier dysfunction and immune dysregulation at these mucosal surfaces leads to the much higher rates of pneumonia, meningitis and severe sepsis seen in resource-limited countries.

• Neisseria lactamica selectively induces mitogenic proliferation of the naive B cell pool via cell surface Ig.

  Authors: Andrew T Vaughan, Louise S Brackenbury, Paola Massari, Victoria Davenport, Andrew Gorringe, Robert S Heyderman, Neil A Williams

  Journal of immunology (Baltimore, Md. : 1950). 09/2010; 185(6):3652-60.

  Neisseria lactamica is a commensal bacteria that colonizes the human upper respiratory tract mucosa during early childhood. In contrast to the closely related opportunistic pathogen NeisseriaNeisseria lactamica is a commensal bacteria that colonizes the human upper respiratory tract mucosa during early childhood. In contrast to the closely related opportunistic pathogen Neisseria meningitidis, there is an absence of adaptive cell-mediated immunity to N. lactamica during the peak age of carriage. Instead, outer membrane vesicles derived from N. lactamica mediate a B cell-dependent proliferative response in mucosal mononuclear cells that is associated with the production of polyclonal IgM. We demonstrate in this study that this is a mitogenic human B cell response that occurs independently of T cell help and any other accessory cell population. The ability to drive B cell proliferation is a highly conserved property and is present in N. lactamica strains derived from diverse clonal complexes. CFSE staining of purified human tonsillar B cells demonstrated that naive IgD(+) and CD27(-) B cells are selectively induced to proliferate by outer membrane vesicles, including the innate CD5(+) subset. Neither purified lipooligosaccharide nor PorB from N. lactamica is likely to be responsible for this activity. Prior treatment of B cells with pronase to remove cell-surface Ig or treatment with BCR-specific Abs abrogated the proliferative response to N. lactamica outer membrane vesicles, suggesting that this mitogenic response is dependent upon the BCR.

• T Cell Memory Response to Pneumococcal Protein Antigens in an Area of High Pneumococcal Carriage and Disease.

  Authors: Marianne W Mureithi, Adam Finn, Martin O Ota, Qibo Zhang, Victoria Davenport, Timothy J Mitchell, Neil A Williams, Richard A Adegbola, Robert S Heyderman

  The Journal of infectious diseases. 10/2009; 200(5):783-793.

  Background. Streptococcus pneumoniae is a leading cause of vaccine-preventable disease worldwide. Pneumococcal protein antigens are currently under study as components of potential vaccines thatBackground. Streptococcus pneumoniae is a leading cause of vaccine-preventable disease worldwide. Pneumococcal protein antigens are currently under study as components of potential vaccines that offer protection against multiple serotypes. We have therefore characterized T cell pneumococcal immunity acquired through asymptomatic carriage. Methods. Peripheral blood mononuclear cells from 40 healthy Gambian adults were stimulated with supernatants derived from S. pneumoniae strain (D39), 2 isogenic mutant strains lacking either pneumolysin or choline binding protein A, and recombinant pneumolysin. Immune responses were measured by cellular proliferation and by interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot and bioplex cytokine assays. Nasopharyngeal swabs were cultured to determine carriage rates. Results. S. pneumoniae nasopharyngeal carriage was detected in 60% of individuals. Both effector and resting (or central) CD4(+) T cell memory were frequently present to a range of pneumococcal antigens. However, the level of the effector memory response did not relate to current nasopharyngeal carriage. Pneumolysin was not immunodominant in these T cell responses but induced a distinct proinflammatory profile (high IFN-gamma, IL-12[p40], and L-17 levels and low IL-10 and IL-13 levels). Conclusions. In this population, T cell-mediated immunological memory potentially capable of pathogen clearance and immune surveillance is common but is not associated with the absolute interruption of pneumococcal carriage. How this naturally acquired immune memory influences pneumococcal vaccine efficacy remains to be determined.

• Absence of mucosal immunity in the human upper respiratory tract to the commensal bacteria Neisseria lactamica but not pathogenic Neisseria meningitidis during the peak age of nasopharyngeal carriage.

  Authors: Andrew T Vaughan, Andrew Gorringe, Victoria Davenport, Neil A Williams, Robert S Heyderman

  Journal of immunology (Baltimore, Md. : 1950). 03/2009; 182(4):2231-40.

  The normal flora that colonizes the mucosal epithelia has evolved diverse strategies to evade, modulate, or suppress the immune system and avoid clearance. Neisseria lactamica and NeisseriaThe normal flora that colonizes the mucosal epithelia has evolved diverse strategies to evade, modulate, or suppress the immune system and avoid clearance. Neisseria lactamica and Neisseria meningitidis are closely related obligate inhabitants of the human upper respiratory tract. N. lactamica is a commensal but N. meningitidis is an opportunistic pathogen that occasionally causes invasive disease such as meningitis and septicemia. We demonstrate that unlike N. meningitidis, N. lactamica does not prime the development of mucosal T or B cell memory during the peak period of colonization. This cannot be explained by the induction of peripheral tolerance or regulatory CD4(+)CD25(+) T cell activity. Instead, N. lactamica mediates a B cell-dependent mitogenic proliferative response that is absent to N. meningitidis. This mitogenic response is associated with the production of T cell-independent polyclonal IgM that we propose functions by shielding colonizing N. lactamica from the adaptive immune system, maintaining immunological ignorance in the host. We conclude that, in contrast to N. meningitidis, N. lactamica maintains a commensal relationship with the host in the absence of an adaptive immune response. This may prolong the period of susceptibility to colonization by both pathogenic and nonpathogenic Neisseria species.

• Impaired maintenance of naturally acquired T cell memory to the meningococcus in individuals with B cell immunodeficiency.

  Authors: Begonia Morales-Aza, Sarah J Glennie, Tomaz Pereira Garcez, Victoria Davenport, Sarah L Johnston, Neil A Williams, Robert S Heyderman

  Blood. 03/2009;

  The importance of T cells in the generation of antigen specific B cell immunity has been extensively described, but the role B cells play in shaping T cell memory is uncertain. In healthyThe importance of T cells in the generation of antigen specific B cell immunity has been extensively described, but the role B cells play in shaping T cell memory is uncertain. In healthy individuals, exposure to Neisseria meningitidis in the upper respiratory tract is associated with the generation of memory T cells in the mucosal and systemic compartments. However, we demonstrate that in B cell deficient subjects with X-linked agammaglobulinemia (XLA), naturally-acquired T cell memory responses to meningococcal antigens are reduced compared with healthy controls. This difference is not seen in T cell memory to an obligate respiratory pathogen, influenza virus. Accordingly, we show that meningococcal antigens upregulate MHC class II, CD40, CD86/80 expression on mucosal and systemic associated B cells and that antigen presentation stimulates T cell proliferation. A similar reduction in N. meningitidis but not influenza antigen-specific T cell memory was seen in subjects with X-linked hyper IgM syndrome (X-HIM), implicating the interaction of CD40-CD40L in this process. Together, these data implicate B cells in the induction and maintenance of T cell memory to mucosal colonizing bacteria such as N. meningitidis, and highlight the importance of B cells beyond antibody production but as a target for immune reconstitution.

• Bacterial toxins as immunomodulators.

  Authors: David S Donaldson, Neil A Williams

  Advances in experimental medicine and biology. 01/2009; 666:1-18.

  Bacterial toxins are the causative agent at pathology in a variety of diseases. Although not always the primary target of these toxins, many have been shown to have potent immunomodulatory effects,Bacterial toxins are the causative agent at pathology in a variety of diseases. Although not always the primary target of these toxins, many have been shown to have potent immunomodulatory effects, for example, inducing immune responses to co-administered antigens and suppressing activation of immune cells. These abilities of bacterial toxins can be harnessed and used in a therapeutic manner, such as in vaccination or the treatment of autoimmune diseases. Furthermore, the ability of toxins to gain entry to cells can be used in novel bacterial toxin based immuno-therapies in order to deliver antigens into MHC Class I processing pathways. Whether the immunomodulatory properties of these toxins arose in order to enhance bacterial survival within hosts, to aid spread within the population or is pure serendipity, it is interesting to think that these same toxins potentially hold the key to preventing or treating human disease.

• Phage-display derived single-chain fragment variable (scFv) antibodies recognizing conformational epitopes of Escherichia coli heat-labile enterotoxin B-subunit.

  Authors: Wen Yuan Chung, Markus Sack, Rachel Carter, Holger Spiegel, Rainer Fischer, Timothy R Hirst, Neil A Williams, Roger F L James

  Journal of immunological methods. 10/2008;

  Previously we have described studies on in vitro pentamer assembly of Escherichia coli (E. coli) derived heat-labile enterotoxin B subunit (EtxB) using conventional monoclonal antibodies (Amin etPreviously we have described studies on in vitro pentamer assembly of Escherichia coli (E. coli) derived heat-labile enterotoxin B subunit (EtxB) using conventional monoclonal antibodies (Amin et al., JBC 1995: 270, 20143-50 and Chung et al., JBC 2006: 281, 39465-70). To extend these studies further we have used phage-display to select single-chain Fragment variable (scFv) antibodies against different forms of the B-subunit. Two clones exhibiting strong and differential binding were chosen for detailed characterization. A comprehensive sequence analysis was performed to assign the framework and complementary-determining regions and a nonsense mutation present in one of these (scFv-B1.3.9) was corrected. Binding analysis showed that scFv-B1.3.9 bound in ELISA to both heat-denatured monomeric B-subunits (EtxB(1)) and also displayed cross-reactivity towards pentameric EtxB (EtxB(5)), although there was no reactivity towards monoganglioside (G(M1)) captured EtxB(5). Another antibody (scFv-B5.2.14) had a different reactivity profile and, in ELISA, bound only to EtxB(5) but not to EtxB(1) or to EtxB(5) captured via G(M1.) Surprisingly, in competition experiments, the assembled pentameric B-subunit inhibited binding of scFv-B5.2.14 to immobilized EtxB(5) only weakly, whereas reduced, but not oxidized, monomeric EtxB(1) was an efficient competitor. These results clearly demonstrate that B1.3.9 and B5.2.14 have different specificities for cryptic epitopes not accessible in the fully assembled G(M1) bound pentameric form of EtxB. Taken together our results show that we were able to successfully isolate and characterize recombinant scFvs that differentially recognize diverse denatured forms or assembly intermediates of the heat-labile enterotoxin B subunit of E. coli.

• Mucosal immunity in healthy adults after parenteral vaccination with outer-membrane vesicles from Neisseria meningitidis serogroup B.

  Authors: Victoria Davenport, Eleanor Groves, Rachel E Horton, Christopher G Hobbs, Terry Guthrie, Jamie Findlow, Ray Borrow, Lisbeth M Naess, Philipp Oster, Robert S Heyderman, Neil A Williams

  The Journal of infectious diseases. 09/2008; 198(5):731-40.

  Nasopharyngeal carriage of meningococcus or related species leads to protective immunity in adolescence or early adulthood. This natural immunity is associated with mucosal and systemic T cellNasopharyngeal carriage of meningococcus or related species leads to protective immunity in adolescence or early adulthood. This natural immunity is associated with mucosal and systemic T cell memory. Whether parenteral Neisseria meningitidis serogroup B (MenB) vaccination influences natural mucosal immunity is unknown. To determine whether parenteral MenB vaccination affects mucosal immunity in young adults and whether this immunity differs from that induced in the blood. Otherwise healthy volunteers were immunized with MenB outer membrane vesicle vaccine before and after routine tonsillectomy. Mucosal and systemic immunity were assessed in 9 vaccinees and 12 unvaccinated control subjects by measuring mononuclear cell proliferation, cytokine production, Th1/Th2 surface marker expression, and antibody to MenB antigens. Parenteral vaccination induced a marked increase in systemic T cell immunity against MenB and a Th1 bias. In contrast, although mucosal T cell proliferation in response to MenB neither increased nor decreased following vaccination, mononuclear cell interferon gamma, interleukin (IL)-5, and IL-10 production increased, and the Th1/Th2 profile lost its Th1 bias. Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.

• The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established autoimmune uveoretinitis.

  Authors: Ben J E Raveney, Claire M Richards, Marie-Laure Aknin, David A Copland, Bronwen R Burton, Emma C Kerr, Lindsay B Nicholson, Neil A Williams, Andrew D Dick

  Investigative ophthalmology & visual science. 06/2008;

  Purpose: To investigate the efficacy of B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Background: Murine experimental autoimmunePurpose: To investigate the efficacy of B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Background: Murine experimental autoimmune uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal-antigen-specific Th1 and Th17 CD4(+) T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T cell activity. Methods: EAU was induced in B10.RIII mice by immunisation with peptide of hIRBP161-180. Disease severity was measured by clinical and histological assessment and functional responses of macrophages (Mphi) and T cells were assessed both in vivo and in in vitro co-cultures. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EAU induction. Results: Pre-immunisation treatment with EtxB protected mice from EAU, limiting both the number and the activation status of retinal infiltrating immune cells. Treatment following EAU induction did not alter disease course, despite suppression of IFN-gamma. Although EtxB treatment of in vitro co-cultures of T cells and Mphi increased IL-10 production, EtxB treatment in vivo increased the proportion and numbers of IL-17-producing CD4(+) cells infiltrating the eye. Conclusion: EtxB pre-immunisation protects mice from EAU induction by inhibiting Th1 responses, but the resulting reduction in IFN-gamma responses by EtxB does not effect infiltration or structural damage in established EAU, where Th17 responses predominate. These data highlight the critical importance of the dynamics of T cell phenotype and infiltration during EAU when considering immunomodulatory therapy.

• Loss of CTL function among high-avidity tumor-specific CD8+ T cells following tumor infiltration.

  Authors: Claire N Janicki, S Rhiannon Jenkinson, Neil A Williams, David J Morgan

  Cancer research. 05/2008; 68(8):2993-3000.

  A major problem in generating effective antitumor CTL responses is that most tumors express self-antigens to which the immune system is rendered unresponsive due to mechanisms of self-toleranceA major problem in generating effective antitumor CTL responses is that most tumors express self-antigens to which the immune system is rendered unresponsive due to mechanisms of self-tolerance induction. CTL precursors (CTLp) expressing high-affinity T-cell receptors (TCR) are often functionally deleted from the repertoire, leaving a residual repertoire of CTLp having only low-affinity TCR. Furthermore, even when unique antigens are expressed, their presentation by dendritic cells (DC) may predispose to peripheral tolerance induction rather than the establishment of CTL responses that kill tumor cells. In this study, we examined both high-avidity (CL4) and low-avidity (CL1) CD8(+) T-cell responses to a murine renal carcinoma expressing, as a neoantigen, high and low levels of the hemagglutinin (HA) protein from influenza virus A/PR/8 H1N1 (PR8; RencaHA(high) and RencaHA(low)). Our data show that, following encounter with K(d)HA epitopes cross-presented by bone marrow-derived DC, low-avidity CL1 cells become tolerized within tumor-draining lymph nodes (TDLN), and in mice bearing either RencaHA(high) or RencaHA(low) tumors, very few form tumor-infiltrating lymphocytes (TIL). In marked contrast, high-avidity CL4 cells differentiate into effector CTL within the TDLN of mice bearing either RencaHA(high) or RencaHA(low) tumors, and although they form TIL in both tumors, they lose CTL effector function. Critically, these results show that anticancer therapies involving either adoptive transfer of high-avidity tumor-specific CTL populations or targeting of preexisting tumor antigen-specific memory CD8(+) T cells could fail due to the fact that CTL effector function is lost following tumor infiltration.

• Tonsil T cell immunity to human papillomavirus in the absence of detectable virus in healthy adults.

  Authors: Christopher G L Hobbs, Eleanor Groves, Victoria Davenport, Michael Bailey, Neil A Williams, Martin A Birchall, Robert S Heyderman

  The Laryngoscope. 04/2008; 118(3):459-63.

  BACKGROUND: Human papillomavirus (HPV) is known to infect the epithelium of the upper aerodigestive tract; however, major questions regarding prevalence and persistence of infection, and theirBACKGROUND: Human papillomavirus (HPV) is known to infect the epithelium of the upper aerodigestive tract; however, major questions regarding prevalence and persistence of infection, and their relation to local immune response, remain unanswered. OBJECTIVES: To evaluate the tonsil T cell immune response to HPV and compare this to the frequency of detectable virus at this site. STUDY DESIGN: A cross-sectional study of cancer-free adults undergoing routine tonsillectomy. METHODS: Mucosal immune responses to recombinant HPV16 L2E6E7 and HPV6 L2E7 antigens were measured by tonsillar T-lymphocyte proliferation assay in 13 subjects. HPV deoxyribonucleic acid (DNA) was assessed by PCR and reverse line-blot hybridization in an expanded population of 44 subjects. RESULTS: Proliferative T-cell responses to HPV16 and HPV6 were identified in all patients. The presence of a CD45RO+ T cell population responsive to HPV6 L2E7 was confirmed in three of six subjects tested. There were no CD45RO+ responses to HPV16 L2E6E7 and no evidence of current or latent HPV infection of the tonsil. CONCLUSIONS: T cell memory to human papillomavirus can be identified in tonsil tissue from an adult population in the absence of concurrent HPV infection. How novel HPV vaccines might augment this preexisting cell-mediated immunity is an essential area for investigation.

• Regulation of Th-1 T cell-dominated immunity to Neisseria meningitidis within the human mucosa.

  Authors: Victoria Davenport, Eleanor Groves, Christopher G Hobbs, Neil A Williams, Robert S Heyderman

  Cellular microbiology. 05/2007; 9(4):1050-61.

  Neisseria meningitidis is commonly carried asymptomatically in the upper respiratory tract and only occasionally invades the bloodstream and meninges to cause disease. Naturally acquired immunityNeisseria meningitidis is commonly carried asymptomatically in the upper respiratory tract and only occasionally invades the bloodstream and meninges to cause disease. Naturally acquired immunity appears protective but the nature of the cellular immune response within the mucosa is uncertain. We show that following in vitro stimulation with N. meningitidis serogroup B (MenB) antigens, approximately 66% of the dividing mucosal CD4(+)CD45RO(+) memory population express the Th1-associated IL18-R while the remainder express CRTH2, a Th2-associated marker. The pro-inflammatory bias of this anti-MenB response is not evident in blood, demonstrating compartmentalization at the induction site; and occurs in the presence or absence of lipopolysacharide indicating that these responses are already fully committed. Depletion of CD25(+) cells reveals suppression of the effector CD4(+) T cell response restricted to the mucosa and most marked in children (i.e. those at greatest risk of disease). Mucosal T-regulatory cell (Treg) activity is partially overcome by blocking the human glucocorticoid-induced TNF receptor (GITR) and is not seen following stimulation with antigens from another mucosal pathogen, influenza virus. Pro-inflammatory, antimeningococcal T cell responses may limit invasive disease at the mucosa but Treg induction while reducing immunopathological damage, may also restrict the effectiveness of the protective response, particularly in children.

• Regulation of intestinal immunity: effects of the oral adjuvant Escherichia coli heat-labile enterotoxin on migrating dendritic cells.

  Authors: Simon W F Milling, Ulf Yrlid, Chris Jenkins, Claire M Richards, Neil A Williams, Gordon MacPherson

  European journal of immunology. 02/2007; 37(1):87-99.

  Escherichia coli heat-labile enterotoxin (Etx) is an oral adjuvant in mice. We show that this is also true for rats. To understand this adjuvant activity we examined lymph dendritic cells (DC)Escherichia coli heat-labile enterotoxin (Etx) is an oral adjuvant in mice. We show that this is also true for rats. To understand this adjuvant activity we examined lymph dendritic cells (DC) migrating from the intestine to mesenteric lymph nodes (MLN) in animals fed Etx. These DC can prime antigen-specific antibody responses. We show that in rats the small intestine contains 7-24 million DC and 8 x 10(5 )of these migrate to MLN each day. Surprisingly, Etx does not stimulate increased migration of lymph DC. However, oral Etx affects the activation, antigen transport and localization of migratory DC. Specifically, expression of CD25 increases on the CD172a(high) subset of lymph DC. Oral Etx also increases the number of CD172a(high) lymph DC containing co-administered ovalbumin. CD172a(high) lymph DC treated with Etx in vitro, or purified from the lymph of animals fed Etx, stimulate stronger proliferative responses from primed T cells. Etx also directs more of the CD172a(high) lymph DC into the central region of the MLN T cell areas. This change in DC localization is associated with an increase in the expression of CCR7. These data help advance our understanding of the role of DC in initiating mucosal immune responses in vivo.

• Mucosal immunity and optimizing protection with meningococcal serogroup B vaccines.

  Authors: Robert S Heyderman, Victoria Davenport, Neil A Williams

  Trends in microbiology. 03/2006; 14(3):120-4.

  Candidate Neisseria meningitidis serogroup B vaccines that are based on outer-membrane vesicles induce protective immunity in adults but provide neither crossprotection for infants nor long-lastingCandidate Neisseria meningitidis serogroup B vaccines that are based on outer-membrane vesicles induce protective immunity in adults but provide neither crossprotection for infants nor long-lasting immunity. We suggest that this lack of vaccine efficacy is not solely because the best antigens are yet to be identified but also results from inappropriate programming of the immune response. Natural carriage of N. meningitidis and related bacteria leads to the development of protective immunity both at the mucosal surface and in the circulation. We propose that vaccine strategies that mimic this natural immunization process would better-optimize vaccine-induced protective immunity. Thus, mucosal immunization before a systemic booster vaccination could provide the solution and reduce the necessity for multiple injections to achieve immunity.

• Protection of non-obese diabetic mice from autoimmune diabetes by Escherichia coli heat-labile enterotoxin B subunit.

  Authors: Thomas O Ola, Neil A Williams

  Immunology. 03/2006; 117(2):262-70.

  Autoimmune diabetes in the non-obese diabetic (NOD) mouse is associated with development of inflammation around the islets at around 4-5 weeks of age, which may be prolonged until frank diabetesAutoimmune diabetes in the non-obese diabetic (NOD) mouse is associated with development of inflammation around the islets at around 4-5 weeks of age, which may be prolonged until frank diabetes begins to occur around 12 weeks of age. Although many interventions can halt disease progression if administration coincides with the beginning of the anti-beta cell response, very few are able to prevent diabetes development once insulitis is established. Here we describe a strategy which blocks cellular infiltration of islets and prevents diabetes. Intranasal treatment with the B-subunit of Escherichia coli heat labile enterotoxin (EtxB), a protein that binds GM1 ganglioside (as well as GD1b, asialo-GM1 and lactosylceramide with lower affinities), protected NOD mice from developing diabetes in a receptor-binding dependent manner. Protection was associated with a significant reduction in the number of macrophages, CD4(+) T cells, B cells, major histocompatibility complex class II(+) cells infiltrating the islets. Despite this, treated mice showed increased number of interleukin-10(+) cells in the pancreas, and a decrease in both T helper 1 (Th1) and Th2 cytokine production in the pancreatic lymph node. Disease protection was also transferred with CD4(+) splenocytes from treated mice. Taken together, these results demonstrated that EtxB is a potent immune modulator capable of blocking diabetes.

• The role of intercellular adhesion molecule-1/LFA-1 interactions in the generation of tumor-specific CD8+ T cell responses.

  Authors: S Rhiannon Jenkinson, Neil A Williams, David J Morgan

  Journal of immunology (Baltimore, Md. : 1950). 04/2005; 174(6):3401-7.

  The activation of naive CD4+ T cells requires both TCR engagement and a second costimulatory signal mediated by the interaction of CD28 with CD80/CD86 expressed on professional APC. However, theThe activation of naive CD4+ T cells requires both TCR engagement and a second costimulatory signal mediated by the interaction of CD28 with CD80/CD86 expressed on professional APC. However, the situation for naive CD8+ T cells is less clear. Although evidence indicates that induction of CD8+ T cell responses is also dependent on professional APC, the ability of some tumors, which do not express CD80/CD86, to induce CTL suggests that other pathways of costimulation exist for the activation of CD8+ T cells. We examined the ability of tumor cells expressing different levels of a tumor-specific Ag to directly prime CD8+ T cells. We demonstrate that CD8+ T cells are directly activated by tumor cells in a CD80/CD86-CD28 independent manner. In this system, costimulation requires ICAM-1/LFA-1 interaction. This results in the generation of CTL capable of inhibiting tumor growth in vivo, and maintaining long-term survival.