Cutting Edge: CTLA-4 on Effector T Cells

CTLA-4 is thought to inhibit effector T cells both intrin-sically, by competing with CD28 for B7 ligands, and ex-trinsically, through the action of regulatory T cells (Tregs). We studied in vivo responses of normal and CTLA-4–deficient Ag-specific murine effector CD4 + T cells. We directly demonstrate that effector T cell-restricted CTLA-4 inhibits T cell responses in a cell-extrinsic manner. Cotransfer experiments show that CTLA-4 on normal effector CD4 + T cells completely abrogates the dramatically increased expansion normally experienced by their CTLA-4–deficient counterparts. Neither the wild-type nor the CTLA-4–deficient T cells express the Treg transcription factor Foxp3 when transferred alone or together. Thus, cell-extrinsic inhibition of T cell responses by CTLA-4 is not limited to Tregs but is also a function of effector T cells. T he T cell transmembrane receptor CTLA-4 is a critical negative regulator of T cell responses (1). Blocking its function increases antitumor T cell responses (2), and anti–CTLA-4 Ab has been approved by the U.S. Food and Drug Administration for treatment of late-stage melanoma (3). Despite prolific investigation, the mechanisms by which CTLA-4 inhibits T cell responses are actively debated (4–6). Initial in vitro experiments showed that ligation of CTLA-4 by cross-linking specific Ab inhibited T cell proliferation and IL-2 production, whereas blocking function with Ab Fab fragments augmented proliferation (7, 8). Nonmutually exclusive cell-autonomous mechanisms by which CTLA-4 is thought to downregulate T cell responses include competition with the CD28 costimulatory receptor for their shared ligands, B7-1 and B7-2; transcriptional inhibition of cell cycle regulators; and inhibition of signal-transduction pathways downstream of TCR (9, 10). Fatal lymphoproliferation and autoimmunity in mice deficient for CTLA-4 exemplify its importance in the physiological negative regulation of T cells (11–13). In contrast to rampant proliferative disease in CTLA-4–de-ficient animals, the healthy phenotype of chimeras of wild-type (WT) and CTLA-4–deficient bone marrow first suggested the existence of a cell-extrinsic mode of CTLA-4 inhibition (14). Experiments involving suppression of colitogenic CD45RB high CD4 + T cells by their CD45RB low counterparts attributed cell-extrinsic CTLA-4 function to Foxp3 + regulatory T cells (Tregs), which constitutively express significantly more surface CTLA-4 than do activated effector T cells (15, 16). Indeed , Treg-specific CTLA-4 deficiency results in decreased suppressive function and causes disease, albeit milder than seen in mice fully deficient in CTLA-4 (17). Blockade of CTLA-4 on both effector T cells and Tregs contributes to antitumor immunity (18), and a vague consensus …