IL-2–Independent and TNF-α–Dependent Expansion of Vβ5+ Natural Regulatory T Cells during Retrovirus Infection

Abstract

Friend virus (FV) infection of mice induces the expansion and activation of regulatory T cells (Tregs) that dampen acute immune responses and promote the establishment and maintenance of chronic infection. Adoptive transfer experiments and the expression of Neuropilin 1 indicate that these cells are predominantly natural Tregs rather than virus-specific conventional CD4+ T cells that converted into induced Tregs. Analysis of Treg TCR Vβ chain usage revealed a broadly distributed polyclonal response with a high proportionate expansion of the Vβ5+ Treg subset, which are known to be responsive to endogenous retrovirus-encoded superantigens. In contrast to the major population of Tregs, the Vβ5+ subset expressed markers of terminally differentiated effector cells, and their expansion was associated with the level of the antiviral CD8+ T cell response rather than the level of FV infection. Surprisingly, the expansion and accumulation of the Vβ5+ Tregs was IL-2 independent but dependent upon TNFα. These experiments reveal a subset-specific Treg induction by a new pathway.

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

“…Surprisingly, no expansion or activation of Tregs was found in the spleens of acutely mCMV-infected mice, in contrast to what is described for FV or lymphocytic choriomeningitis virus (LCMV) infection ( Fig. 1b and c) (10)(11)(12). Additionally, no expansion of the V␤5 ϩ CD4 ϩ Foxp3 ϩ Tregs, which recognize self-superantigens expressed by endogenous mouse mammary tumor virus, were detectable in mCMV-infected mice (8,10,11; data not shown).…”

“…1b and c) (10)(11)(12). Additionally, no expansion of the V␤5 ϩ CD4 ϩ Foxp3 ϩ Tregs, which recognize self-superantigens expressed by endogenous mouse mammary tumor virus, were detectable in mCMV-infected mice (8,10,11; data not shown). Furthermore, Tregs from mCMV-infected mice displayed the same phenotype as Tregs from naive animals (Fig.…”

“…Previously, it had been shown that the activation and expansion of Tregs during FV infection were not dependent on FV antigens but rather were initiated by self-antigens and cytokines, like interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-␣) (8,10). Hence, no FV-specific Tregs were found during FV infection (10).…”

“…These effector T cells play a major role in initiating the activation and expansion of different subsets of Tregs (8,10,17).…”

Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling

“…Recently we demonstrated that FV infection induced disproportionately greater expansion of Tregs expressing the T cell receptor (TCR) Vβ5 chain compared to Tregs expressing other Vβ chains (17). Investigation revealed that the proliferation of this subpopulation was driven by a mechanism distinct from other Tregs.…”