CTLA-4 Engagement Acts as a Brake on CD4+ T Cell Proliferation and Cytokine Production but Is Not Required for Tuning T Cell Reactivity in Adaptive Tolerance

Abstract

Adaptive tolerance is the physiologic down-regulation of T cell responsiveness in the face of persistent antigenic stimulation. In this study, we examined the role of CTLA-4 in this process using CTLA-4-deficient and wild-type TCR transgenic, Rag2−/−, CD4+ T cells transferred into a T cell-deficient, Ag-expressing host. Surprisingly, we found that the tuning process of adoptively transferred T cells could be induced and the hyporesponsive state maintained in the absence of CTLA-4. Furthermore, movement to a deeper state of anergy following restimulation in vivo in a second Ag-bearing host was also unaffected. In contrast, CTLA-4 profoundly inhibited late T cell expansion in vivo following both primary and secondary transfers, and curtailed IL-2 and IFN-γ production. Removal of this braking function in CTLA-4-deficient mice following Ag stimulation may explain their lymphoproliferative dysregulation.

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

“…On the one hand, CTLA-4 was critical for the induction of tolerance to tissue Ag and, in these conditions, self-Ag was found to be alone sufficient to initiate pathologic autoimmunity in lymphocyte-depleted recipients reconstituted with self-Ag-specific CTLA-4-deficient CD4 ϩ T cells (40). On the other hand, the same CTLA-4-deficient T cells transferred into systemic Ag-expressing mice became just as hyporesponsive as wild-type cells and adapted their response to the persistent presence of their Ag (41,42). Thus, CTLA-4 does not appear to be as important for T cell adaptation to systemic Ags as it is for tolerance to tissue-restricted Ag.…”

Cellular and genetic mechanisms of self tolerance and autoimmunity

“…Expression of another inhibitory receptor, cytotoxic T-lymphocyte antigen 4 (CTLA4), is induced at a high threshold of TCR self reactivity and inhibits T-cell activation by competing with CD28 for ligation with B7 molecules and by transmitting inhibitory signals 48,52,53 . Lack of CTLA4 causes massive accumulation of self-reactive T cells in peripheral lymphoid and nonlymphoid tissues, both by disrupting intrinsic regulation of TCR-induced proliferation 53,54 and by impairing the suppressive function of T R cells. Subtle functional variants of the CTLA4 gene are associated with susceptibility to thyroid autoimmunity and type 1 diabetes in humans and mice 55 .…”

Rapid proliferation of activated lymph node CD4+ T cells is achieved by greatly curtailing the duration of gap phases in cell cycle progression

“…The T cells that can respond to a single antigen are very limited [2], so rapid proliferation is required to enable a quick immune response. Several reports have indicated that CD4 + T cells could duplicate as quickly as every 5 to 6 h in vivo [3][4][5], which implies a very rapid completion of the cell cycle. The nature of this cycle has yet to be well characterized.…”