Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells

Abstract

Negative as well as positive co-stimulation appears to play an important role in controlling T cell activation. CTLA-4 has been proposed to negatively regulate T cell responses. CTLA-4-deficient mice develop a lymphoproliferative disorder, initiated by the activation and expansion of CD4+ T cells. To assess the function of CTLA-4 on CD8+ T cells, CTLA-4(-/-) animals were crossed to an MHC class I-restricted 2C TCR transgenic mouse line. We demonstrate that although the primary T cell responses were similar, the CTLA-4-deficient 2C TCR+ CD8+ T cells displayed a greater proliferative response upon secondary stimulation than the 2C TCR+ CD8+ T cells from CTLA-4 wild-type mice. These results suggest that CTLA-4 regulates antigen-specific memory CD8+ T cell responses.

Blockade of T Cell Activation Using a Surface-Linked Single-Chain Antibody to CTLA-4 (CD152)

“…The concept of a protracted role for CTLA-4 in shaping the magnitude, nature, and duration of an ongoing immune response is compatible with its persistent expression in activated helper and cytotoxic T cells (51)(52)(53)(54)(55), in memory T cells (56), and in T cellderived clones of a variety of phenotypes (55,57). With this in mind, experiments were performed using preactivated T cells and T cell subsets (see Materials and Methods).…”

“…Of note, we could also clearly observe negative regulation of Agspecific, preactivated CD8 ϩ T cells following CTLA-4/TCR coengagement using the 2C T cells. Thus, although recent studies have shown that CLTA-4 may not exert significant effects during primary CD8 ϩ T cell activation (52,65), our results and those of others (53,54) suggest that CTLA-4-mediated negative regulation of CD8 ϩ T cells may occur both indirectly, through inhibition of CD4 ϩ helper functions, and directly, through inhibition of expansion and cytokine production during secondary Ag encounters.…”

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

“…Whether such small numbers of Treg in Tg mice are functional and sufficient for preventing the induction of the lymphoproliferative disorder remains to be determined. It appears to be established that CTLA-4 does not affect thymocyte differentiation [7][8][9][10]. Still, this is only based on the observation that three different TCR-Tg mice (HY-Tg, LCMV-Tg, and DO11.10 TCR-Tg mice) crossed with CTLA-4 -/-mice did not reveal any gross defect in thymic positive/negative selections [7][8][9][10].…”

“…It appears to be established that CTLA-4 does not affect thymocyte differentiation [7][8][9][10]. Still, this is only based on the observation that three different TCR-Tg mice (HY-Tg, LCMV-Tg, and DO11.10 TCR-Tg mice) crossed with CTLA-4 -/-mice did not reveal any gross defect in thymic positive/negative selections [7][8][9][10]. Consistent with these observations, when we crossed FLTg or TR-Tg mice with DO11.10 TCR-Tg or HY-Tg mice and analyzed thymocyte selection, we did not find any significant alternations of overall thymocyte development (unpublished observation).…”

“…It has been suggested that this lymphoproliferative disorder in CTLA-4 -/-mice is induced by polyclonal activation of peripheral T cells and that it is not due to a defect in the elimination of autoreactive T cells in the thymus [7][8][9][10], providing evidence for the in vivo function of CTLA-4 as a negative regulator of T cell responses [5,6]. However, the conclusion that CTLA-4 does not influence thymic selection was based mainly on the analyses of thymocyte development in TCR-transgenic (Tg) Â CTLA-4-deficient mice [7][8][9][10].…”