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

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 TH1 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 TH1-mediated immune responses. We and others have shown that, in TH1 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 TH1 cells and for effector functions of TH1 cells. We have found that deletion of Gadd45b and Gadd45g genes in mice results in a drastically reduced number of TH1 cells against Listeria monocytogenes. The critical role of Gadd45b and Gadd45g in TH1 responses in this acute infectious model has led us to hypothesize that they promote TH1-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 TH1 cells, we were surprised to see that Gadd45b deletion resulted in exacerbated chronic phase of EAE. In contrast to the reduction of TH1 cells we saw in acute L. monocytogenes infection, during the chronic phase of EAE we observed increased TH1 cells in the inflamed CNS when Gadd45b was deleted. Gadd45b deletion also resulted in enlarged spleens in older mice. Gadd45b/Gadd45g 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 "doubleedged sword" in TH1-type immune responses to ensure a prompt, robust but self-limiting TH1 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 TH1 and TH2 cells. There are more effector TH2 cells than TH1 cells that undergo autophagy. We have used RNAi strategy to "knockdown" autophagy in TH2 cell lines and found that autophagy is required for growth factor-withdrawal cell death.