Immunity towards intracellular pathogens is often dependent upon the generation of CD8(+) memory T cells, which provide long-lasting and effective protection. Over the past few years, we have gained novel insights into the heterogeneity of CD8(+) T cells, time points of lineage commitment, and lineage relationships between subpopulations. These studies suggest that memory CD8(+) T cells progressively develop from naïve cells early during the immune response and further differentiate unidirectionally into short-living effector cells. We have also learnt that different memory subsets play distinct roles in conferring protection: whereas effector memory T cells are able to provide immediate protection but are not necessarily maintained long-term, central memory T cells have the potential for constant self-renewal. Thus, neither subset really fulfills all criteria of memory. As protective effector memory cells can develop from central memory cells, vaccination strategies should focus on induction of a balanced ratio of the two memory T cell subsets.
"As a consequence, they are regarded as powerful mediators of immune protection from reinfection. In keeping with this, protective immunity by CD8 + memory T cells has been demonstrated in various experimental models of systemic infection, such as Listeria monocytogenes , lymphocytic choriomeningitis virus (LCMV), and the malaria parasite Plasmodium berghei (Bachmann et al., 1997, 2005; Wherry et al., 2003; Badovinac et al., 2005; Huster et al., 2006; Schmidt et al., 2008). Importantly, T cell immunity in these cases of systemic infection is long-lived and can be conferred to naïve animals by the adoptive transfer of pathogenspecific CD8 + memory T cells (Lau et al., 1994). "
[Show abstract][Hide abstract] ABSTRACT: Microbial infection primes a CD8(+) cytotoxic T cell response that gives rise to a long-lived population of circulating memory cells able to provide protection against systemic reinfection. Despite this, effective CD8(+) T cell surveillance of barrier tissues such as skin and mucosa typically wanes with time, resulting in limited T cell-mediated protection in these peripheral tissues. However, recent evidence suggests that a specialized subset of CD103(+) memory T cells can permanently lodge and persist in peripheral tissues, and that these cells can compensate for the loss of peripheral immune surveillance by circulating memory T cells. Here, we review evolving concepts regarding the generation and long-term persistence of these tissue-resident memory T cells (T(RM)) in epithelial and neuronal tissues. We further discuss the role of T(RM) cells in local infection control and their contribution to localized immune phenomena, in both mice and humans.
Frontiers in Immunology 11/2012; 3:340. DOI:10.3389/fimmu.2012.00340
"TEMC preferentially home to peripheral tissues and respond to antigen encounter with immediate effector function but poor numeric expansion . In contrast, TCMC home to lymphoid organs, can vigorously expand upon antigen reencounter and are therefore potentially assigned to the crucial T cell population that confers long-lasting protective immunity against microbial pathogens . However, proliferative capacity does not necessarily correlate with protection against infection, since TCMC-like CD8 T cells induced by vaccination with heat-killed L. monocytogenes reveal vigorous proliferation and expansion after challenge with live Listeria, but do not protect against listeriosis as determined by clearance of the bacteria . "
[Show abstract][Hide abstract] ABSTRACT: The Salmonella type III secretion system (T3SS) efficiently translocates heterologous proteins into the cytosol of eukaryotic cells. This leads to an antigen-specific CD8 T-cell induction in mice orally immunized with recombinant Salmonella. Recently, we have used Salmonella's T3SS as a prophylactic and therapeutic intervention against a murine fibrosarcoma. In this study, we constructed a recombinant Salmonella strain translocating the immunogenic H-2D(b)-specific CD8 T-cell epitope VILTNPISM (KDR2) from the murine vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 is a member of the tyrosine protein kinase family and is upregulated on proliferating endothelial cells of the tumor vasculature. After single orogastric vaccination, we detected significant numbers of KDR2-tetramer-positive CD8 T cells in the spleens of immunized mice. The efficacy of these cytotoxic T cells was evaluated in a prophylactic setting to protect mice from challenges with B16F10 melanoma cells in a flank tumor model, and to reduce dissemination of spontaneous pulmonary melanoma metastases. Vaccinated mice revealed a reduction of angiogenesis by 62% in the solid tumor and consequently a significant decrease of tumor growth as compared to non-immunized mice. Moreover, in the lung metastasis model, immunization with recombinant Salmonella resulted in a reduction of the metastatic melanoma burden by approximately 60%.
PLoS ONE 04/2012; 7(4):e34214. DOI:10.1371/journal.pone.0034214 · 3.23 Impact Factor
"Collectively, these data suggest that primary memory CD8 + T cells undergo more vigorous proliferation than secondary memory CD8 + T cells regardless of the infectious agent. However, in contrast to some previous suggestions (Wherry et al., 2003b), but not others (Huster et al., 2006; Lauvau et al., 2001), this difference in proliferative potential does not always translate into providing greater protection by a memory CD8 + T cell population because secondary memory CD8 + T cells proliferate less but protect better against acute infections with LM, LCMV, or VacV (Figure 1). It has been demonstrated that primary CD62L hi (central memory [Tcm]) CD8 + T cells are better than primary CD62L lo (effector memory [Tem]) cells at clearing LCMV clone 13 (Wherry et al., 2003b). "
[Show abstract][Hide abstract] ABSTRACT: Infection or vaccination confers heightened resistance to pathogen rechallenge because of quantitative and qualitative differences between naive and primary memory T cells. Herein, we show that secondary (boosted) memory CD8+ T cells were better than primary memory CD8+ T cells in controlling some, but not all acute infections with diverse pathogens. However, secondary memory CD8+ T cells were less efficient than an equal number of primary memory cells at preventing chronic LCMV infection and are more susceptible to functional exhaustion. Importantly, localization of memory CD8+ T cells within lymph nodes, which is reduced by antigen restimulation, was critical for both viral control in lymph nodes and for the sustained CD8+ T cell response required to prevent chronic LCMV infection. Thus, repeated antigen stimulation shapes memory CD8+ T cell populations to either enhance or decrease per cell protective immunity in a pathogen-specific manner, a concept of importance in vaccine design against specific diseases.
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