In 2014 we made novel discoveries in our investigations 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. We discovered a novel subset of natural regulatory T cells (Tregs) that expand disproportionately in response to infection with Friend virus (FV). These Tregs bear Vb5+ T cell receptors, which are unique because of their known specificity for a superantigen (Sag) encoded by an endogenous retrovirus. Our results demonstrated that these superantigen-reactive Tregs had the unusual characteristic of being independent of IL-2 during FV-induced expansion. Instead, the expansion of the Vb5+ Tregs was dependent on activated CD8+ T cells, which are the targets of their suppression. Furthermore, their expansion was also dependent on TNFa and could be blocked by TNFa;neutralization. These results demonstrated a new pathway of Treg expansion and two-way intercellular communication between Tregs and activated CD8+ T cells. We followed up on this discovery to investigate the mechanism of communication between the activated CD8+ T cells and the Vb5+ Tregs. We found that the dependence of Vb5+ Tregs on activated CD8+ T cells was connected to their dependence on TNFa. Activated CD8+ T cells transiently up-regulate membrane bound TNFa, which induces Vb5+ Treg expansion by binding to their TNFR2 receptors. Only Tregs expressing TNFR2 were responsive to TNFa and we could block their responses by neutralizing TNFa. In contrast, the Treg expansion could be induced by treatment with a synthetic TNFR2 ligand. Furthermore, down-regulating the Vb5+ Treg response significantly improved CD8+ T cell function. These experiments demonstrate a method to modulate a subset of highly functional Tregs with implications not only for the treatment of viral infections but also autoimmune diseases.

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6
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2014
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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
Thorborn, Georgina; Ploquin, Mickaƫl 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
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
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
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
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
Lavender, Kerry J; Pang, Wendy W; Messer, Ronald J et al. (2013) BLT-humanized C57BL/6 Rag2-/-?c-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood 122:4013-20
Harper, Michael S; Barrett, Bradley S; Smith, Diana S et al. (2013) IFN-? treatment inhibits acute Friend retrovirus replication primarily through the antiviral effector molecule Apobec3. J Immunol 190:1583-90
Kubinak, J L; Ruff, J S; Cornwall, D H et al. (2013) Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence. Genes Immun 14:365-72

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