Keeping CD4+ T cells under control
Two members of the growth arrest and DNA damage-inducible (Gadd45) family have been found to prevent CD4+ T cells from mediating autoimmunity
CD4+ T cells in the periphery are tightly controlled because inappropriate cell division, differentiation into effector cells or cell survival could lead to autoimmunity. A recent study, published in The Journal of Experimental Medicine, now shows that GADD45 (growth arrest and DNA-damage-inducible 45) and GADD45 provide one mechanism to keep peripheral CD4+ T cells under control.
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GADD45 and GADD45 have previously been shown to be crucial for the initiation of T helper 1 (TH1)-cell immune responses and this has been attributed to their effect on p38-mitogen-activated protein kinase. However, in other cell types, they have a role in regulating cell-cycle progression and cell death; so, Liu et al. set out to investigate the role of GADD45 in regulating T-cell proliferation. Following stimulation through the T-cell receptor, GADD45-deficient T cells underwent more rounds of cell division than GADD45-sufficient control T cells. Similarly, when stimulated with interleukin-12 (IL-12) and IL-18, GADD45-deficient TH1 cells divided more times than control cells. In addition, GADD45-deficient TH1 cells showed increased resistance to activation-induced cell death (AICD).
Consistent with a role for GADD45 in controlling T-cell proliferation and susceptibility to AICD, GADD45-deficient mice were more susceptible than control mice to experimental autoimmune encephalomyelitis (EAE). This increase in disease was caused by a T-cell defect because recombination-activating gene 1 (RAG1)-deficient recipients of GADD45-deficient CD4+ T cells were also more susceptible to disease than recipients of wild-type control cells; and it was associated with TH1-cell infiltration of the central nervous system.
Consistent with a synergistic role for GADD45 and GADD45 in regulating T-cell proliferation and susceptibility to AICD, mice lacking both GADD45 and GADD45 had increased numbers of CD4+ T cells in the spleen, compared with mice lacking either GADD45 or GADD45. Furthermore, sera from the Gadd45b-/-Gadd45g-/- mice contained autoantibodies specific for double-stranded DNA and histones, whereas these autoantibodies were absent from the sera of Gadd45b-/- and wild-type mice.
This study indicates that GADD45 and GADD45 are not only important for initiating immune responses but that they also provide an important control mechanism for keeping CD4+ T cells from mediating autoimmunity. Future studies will need to define the molecular mechanisms by which these molecules mediate these apparently opposing effects, and as the authors suggest, this might provide new therapeutic targets for the treatment of autoimmune disease.
Karen Honey
References
- Liu, L. et al. Gadd45 and Gadd45 are critical for regulating autoimmunity. J. Exp. Med. 202, 1341–1348 (2005) | Article | PubMed |
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