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.

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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
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; 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
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(-/-)γc(-/-)CD47(-/-) background. J Immunol Methods 407:127-34
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
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
Myers, Lara; Joedicke, Jara J; Carmody, Aaron B et al. (2013) IL-2-independent and TNF-α-dependent expansion of Vβ5+ natural regulatory T cells during retrovirus infection. J Immunol 190:5485-95
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
Harper, Michael S; Barrett, Bradley S; Smith, Diana S et al. (2013) IFN-α treatment inhibits acute Friend retrovirus replication primarily through the antiviral effector molecule Apobec3. J Immunol 190:1583-90
Lavender, Kerry J; Pang, Wendy W; Messer, Ronald J et al. (2013) BLT-humanized C57BL/6 Rag2-/-γc-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood 122:4013-20

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