Apaf1 Plays a Negative Regulatory Role in T Cell Responses by Suppressing Activation of Antigen-Stimulated T Cells

PLoS One. 2018 Mar 29;13(3):e0195119. doi: 10.1371/journal.pone.0195119. eCollection 2018.

Abstract

Apaf1 is a critical component of the apoptosome and initiates apoptosis downstream mitochondrial damages. Although the importance of Apaf1 in embryonic development was shown, the role of Apaf1 in immune responses, especially T cell responses, has yet to be elucidated. We generated T cell-specific Apaf1-deficient mice (Lck-Cre-Apaf1f/f mice) and examined the antigen-specific delayed-type hypersensitivity (DTH). Lck-Cre-Apaf1f/f mice exhibited exacerbation of DTH responses as compared with Apaf1-sufficient control mice. In Lck-Cre-Apaf1f/f mice, antigen-specific T cells proliferated more, and produced more inflammatory cytokines than control T cells. Apaf1-deficient T cells from antigen-immunized mice showed higher percentages of activation phenotypes upon restimulation in vitro. Apaf1-deficient T cells from naive (non-immunized) mice also showed higher proliferation activity and cytokine production over control cells. The impact of Apaf1-deficiency in T cells, however, was not restored by a pan-caspase inhibitor, suggesting that the role of Apaf1 in T cell responses was caspase-independent/non-apoptotic. These data collectively demonstrated that Apaf1 is a negative regulator of T cell responses and implicated Apaf1 as a potential target for immunosuppressive drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptotic Protease-Activating Factor 1 / physiology*
  • Cells, Cultured
  • Hypersensitivity, Delayed / immunology*
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes / immunology*

Substances

  • APAF1 protein, human
  • Apoptotic Protease-Activating Factor 1

Grant support

This work was in part supported by JSPS KAKENHI Grant Number JP16K08842 (H. Y., http://www.jsps.go.jp/english/, for data collection and analysis) and by the Naito Foundation (H. Y., https://www.naito-f.or.jp/en/, for data collection).