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

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-gamma production. Removal of this braking function in CTLA-4-deficient mice following Ag stimulation may explain their lymphoproliferative dysregulation.