Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2011; 108(9):3677-82. DOI: 10.1073/pnas.1100213108
Source: PubMed


Regulatory T cells (Treg) play critical roles in the modulation of immune responses to infectious agents. Further understanding of the factors that control Treg activation and expansion in response to pathogens is needed to manipulate Treg function in acute and chronic infections. Here we show that chronic, but not acute, infection of mice with lymphocytic choriomeningitis virus results in a marked expansion of Foxp3(+) Treg that is dependent on retroviral superantigen (sag) genes encoded in the mouse genome. Sag-dependent Treg expansion was MHC class II dependent, CD4 independent, and required dendritic cells. Thus, one unique mechanism by which certain infectious agents evade host immune responses may be mediated by endogenous Sag-dependent activation and expansion of Treg.

Download full-text


Available from: Deborah Dacek Glass, Oct 05, 2015
24 Reads
  • Source
    • "WT and DEREG mice were treated with DT on days 10 and 11 following CL-13 infection. Recent work has indicated that the number of Tregs increase after day 10 post-infection Punkosdy et al., 2011, thus day 10 was chosen for depletion. Weight loss and survival were monitored daily following infection (Fig. 6). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulatory T cells (Tregs) play a critical role in maintaining tissue homeostasis and preventing the development of immunopathology. Depletion of REGulatory T cell (DEREG) mice express a diphtheria toxin receptor (DTR)-eGFP transgene under the control of the Foxp3 promoter allowing for Treg depletion following diphtheria toxin (DT) administration. DEREG mice have been utilized to investigate the role of Tregs in a wide range of disease settings. Administration of DT to naïve DEREG mice resulted in the rapid depletion of Foxp3+ Tregs from the peripheral blood. However, by day 4 post-DT administration, a GFP− Foxp3+ Treg population emerged that lacked expression of the DTR transgene and was resistant to further depletion by additional DT treatment. We further evaluated the impact of Treg depletion during both acute and chronic viral infections. Similar to naïve mice, Treg numbers rapidly rebounded during an inflammatory setting following an acute viral infection. DT treatment of both WT and DEREG mice following both acute and chronic viral infections induced exacerbated disease as compared to PBS-treated controls. Furthermore, following a chronic systemic viral infection, DT treatment resulted in nearly 100 percent mortality in both WT and DEREG mice while the PBS-treated controls survived. Our results demonstrate that Treg depletion in DEREG mice is transient and that DT administration can have adverse effects during virus-induced inflammation and highlights the critical need to include DT-treated WT mice when using DTR models to control for DT-mediated toxicity.
    Journal of immunological methods 04/2014; 406. DOI:10.1016/j.jim.2014.03.005 · 1.82 Impact Factor
  • Source
    • "In addition to modulation of the conventional population of CD8+ and CD4+ T cells, Mtv have been demonstrated to influence the immune system during viral infection via expansion of a particular subset of CD4+ T cells expressing the transcription factor Foxp3. Murine infection with the clone 13 isolate of lymphocytic choriomeningitis virus (LCMV) represents a model of chronic viral infection, in which T cell exhaustion results in infection virtually for life (85, 86). Infection of mice with LCMV clone 13 resulted in the selective expansion of a TCR Vβ specific population of Foxp3+ regulatory T cells (Treg) (87). The expansion of TCR Vβ5+ Treg was determined to be MHC class II-dependent, CD4-independent, and secondary to stimulation by the Mtv-9-encoded Sag. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV) and endogenous (Mtv) forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted. Historically, Mtv have been appreciated for their role in shaping the T cell repertoire during thymic development via negative selection. In addition, more recent work has demonstrated a larger role for Mtv in modulating host immune responses due to its peripheral expression. The influence of Mtv on host response has been observed during experimental murine models of Polyomavirus- and ESb-induced lymphoma as well as Leishmania major and Plasmodium berghei ANKA infection. Decreased susceptibility to bacterial pathogens and virus-induced tumors has been observed among mice lacking all Mtv. We have also demonstrated a role for Mtv Sag in the expansion of regulatory T cells following chronic viral infection. The aim of this review is to summarize the latest research in the field regarding peripheral expression of Mtv with a particular focus on their role and influence on the immune system, infectious disease outcome, and potential involvement in tumor formation.
    Frontiers in Oncology 11/2013; 3:287. DOI:10.3389/fonc.2013.00287
  • Source
    • "During chronic lymphocytic choriomeningitis virus (LCMV) infection, Treg cells have been shown to recognize a self-antigen rather than a virus-specific antigen (Punkosdy et al., 2011). This finding may reflect the fact that thymically derived Treg cells are selected by high-affinity interactions with self-antigens within the thymus (Bautista et al., 2009; DiPaolo and Shevach, 2009) and therefore have a propensity for recognizing self-antigens in the periphery (Hsieh et al., 2004, 2006; Killebrew et al., 2011; Korn et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Thymically derived Foxp3(+) regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope-defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3 weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity.
    Immunity 06/2013; 38(6). DOI:10.1016/j.immuni.2013.06.003 · 21.56 Impact Factor
Show more