In 2013 we continued our investigation into the role of regulatory T cells in the establishment and maintenance of chronic retroviral infections. Two papers in peer-reviewed journals were published describing our findings. 1. We discovered a novel subset of regulatory T cells that acted in an IL-2 independent, TNF alpha-dependent manner. We also found that the expansion of these regulatory T cells during retroviral infection was dependent not on virus infection per se, but rather on the CD8+ T cell response to the infection. This information opens new avenues for therapeutic interventions to modulate Treg responses. 2. Previous results from our lab demonstrated a strong role for regulatory T cells in suppressing immune responses to retroviral infection and allowing chronic infections to become established. Those studies primarily focused on suppression of CD8+ T cells. In collaboration with the Dittmer lab we showed this year that regulatory T cells also had suppressive effects on virus-specific CD4(+) T cell responses in vivo, affecting both their proliferation and their cytokine production. These findings highlight the important role of Tregs in retroviral infections and point to avenues of therapeutic intervention.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$267,620
Indirect Cost
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State
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Messer, Ronald J; Lavender, Kerry J; Hasenkrug, Kim J (2014) Mice of the resistant H-2(b) haplotype mount broad CD4(+) T cell responses against 9 distinct Friend virus epitopes. Virology 456-457:139-44
Halemano, Kalani; Guo, Kejun; Heilman, Karl J et al. (2014) Immunoglobulin somatic hypermutation by APOBEC3/Rfv3 during retroviral infection. Proc Natl Acad Sci U S A 111:7759-64
Lavender, Kerry J; Messer, Ronald J; Race, Brent et al. (2014) Production of bone marrow, liver, thymus (BLT) humanized mice on the C57BL/6 Rag2(-/-)?c(-/-)CD47(-/-) background. J Immunol Methods 407:127-34
Thorborn, Georgina; Ploquin, Mickael J; Eksmond, Urszula et al. (2014) Clonotypic Composition of the CD4+ T Cell Response to a Vectored Retroviral Antigen Is Determined by Its Speed. J Immunol 193:1567-77
Joedicke, Jara J; Myers, Lara; Carmody, Aaron B et al. (2014) Activated CD8+ T cells induce expansion of V?5+ regulatory T cells via TNFR2 signaling. J Immunol 193:2952-60
Li, Sam X; Barrett, Bradley S; Heilman, Karl J et al. (2014) Tetherin promotes the innate and adaptive cell-mediated immune response against retrovirus infection in vivo. J Immunol 193:306-16
Joedicke, Jara J; Zelinskyy, Gennadiy; Dittmer, Ulf et al. (2014) CD8+ T cells are essential for controlling acute friend retrovirus infection in C57BL/6 mice. J Virol 88:5200-1
Manzke, Nora; Akhmetzyanova, Ilseyar; Hasenkrug, Kim J et al. (2013) CD4+ T cells develop antiretroviral cytotoxic activity in the absence of regulatory T cells and CD8+ T cells. J Virol 87:6306-13
Myers, Lara; Hasenkrug, Kim J (2009) Retroviral immunology: lessons from a mouse model. Immunol Res 43:160-6
Myers, Lara; Messer, Ronald J; Carmody, Aaron B et al. (2009) Tissue-specific abundance of regulatory T cells correlates with CD8+ T cell dysfunction and chronic retrovirus loads. J Immunol 183:1636-43

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