The molecular mechanisms that control function and death of effector CD4⁺ T cells

Abstract

This review features two areas of our research interests. First, our laboratory is interested in elucidating the molecular mechanisms that control generation, effector function, and fate of T_H1 cells during inflammatory responses. We have been particularly interested in the role of the growth arrest and DNA damage-inducible protein 45 (GADD45) gene family in T_H1-mediated immune responses. We and others have shown that, in T_H1 cells, Gadd45b and Gadd45g are induced by TCR signaling or IL-12 and IL-18. Gadd45b and Gadd45g are very important for the activation of p38 MAP kinases in T_H1 cells and for effector functions of T_H1 cells. We have found that deletion of Gadd45b and Gadd45g genes in mice results in a drastically reduced number of T_H1 cells against Listeria monocytogenes. The critical role of Gadd45b and Gadd45g in T_H1 responses in this acute infectious model has led us to hypothesize that they promote T_H1-mediated autoimmune diseases. We therefore decided to test this hypothesis in experimental allergic encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Expecting low numbers of T_H1 cells, we were surprised to see that Gadd45b deletion resulted in exacerbated chronic phase of EAE. In contrast to the reduction of T_H1 cells we saw in acute L. monocytogenes infection, during the chronic phase of EAE we observed increased T_H1 cells in the inflamed CNS when Gadd45b was deleted. Gadd45b deletion also resulted in enlarged spleens in older mice. Gadd45b/Gadd45g double-deficiency further aggravated this phenotype and resulted in greatly enlarged spleens in older mice compared with Gadd45b single deletion. The enlargement of spleens was due to the accumulation of CD4⁺ T cells with an activated phenotype and B cells. In addition, we have found that Gadd45b and Gadd45g inhibit proliferation and promote apoptosis of activated CD4⁺ T cells. Therefore, Gadd45b and Gadd45g play a critical role as a molecular “double-edged sword” in T_H1-type immune responses to ensure a prompt, robust but self-limiting T_H1 response. The second area of research in our laboratory focuses on the role of autophagy in T cells. We have recently discovered that autophagy is induced in T_H1 and T_H2 cells. There are more effector T_H2 cells than T_H1 cells that undergo autophagy. We have used RNAi strategy to “knockdown” autophagy in T_H2 cell lines and found that autophagy is required for growth factor-withdrawal cell death.