Blockade of CTLA-4 on CD4 ⁺CD25 ⁺ regulatory T cells abrogates their function in vivo

Abstract

Naturally occurring CD4 ⁺ T _R cells that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis preventing immune pathological responses to self and foreign antigens. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for T _R in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in T _R function. Using a colitis transfer model, we previously showed that anti-CTLA-4 mAb treatment abrogates suppression of colitis mediated by CD4 ⁺ CD25 ⁺ T _R. Here we demonstrate that anti-CTLA-4 mAb treatment inhibits T _R function via direct effects on CTLA-4 expressing T _R cells, and not via hyper-activation of colitogenic T cells. Although anti-CTLA-4 mAb treatment completely inhibits T _R function, it does not affect T _R cell expansion, persistence or homing to the gut-associated lymphoid tissue, indicative of the blockade of a signal required for T _R cell activity. In contrast to the striking effect of the antibody, CTLA-4 deficient mice can produce functional T _R cells, suggesting that compensatory mechanisms can develop. This study provides direct evidence that CTLA-4 has a specific, non-redundant role in the function of normal regulatory T cells. This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break T _R-mediated self-tolerance.