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CD4-Dependent Signaling Is Required for a Late Checkpoint during Th2 Development Associated with Resistance to Activation-Induced Cell Death¹

Zohreh Tatari-Calderone^*, Jennifer L. Brogdon, Kevin W. Tinsley^*, Anahita Ramezani^* and David Leitenberg^2,*,

^* Department of Immunology, The George Washington University, Washington, DC 20037; Department of Immunobiology, Yale University, New Haven, CT 06520; and Department of Pediatrics, The George Washington University and Childrens Research Institute, Childrens National Medical Center, Washington, DC 20037

Previous studies have found that class II-restricted T cells from CD4-deficient mice reconstituted with a tail-less CD4 transgene have a specific defect in the development of Th2 effector cells; however, the reason for this defect was not clear. Following stimulation with a high potency peptide and exogenous IL-4, CD4-dependent signaling is required for optimal generation of a Th2 effector population. However, initial IL-4 and GATA-3 transcription is appropriately induced, suggesting that the initial stages of Th2 development are intact and independent of CD4 after priming with a strong agonist peptide. In addition to the defect in Th2 development, CD4 mutant T cells are also relatively resistant to activation-induced cell death (AICD). Furthermore, inhibition of AICD in wild-type T cells causes a defect in Th2 development similar to that seen in the CD4 mutant T cells. These data support the hypothesis that CD4-dependent signaling pathways regulate a distinct checkpoint in the expansion and commitment phase of Th2 development, which is related to dysregulation of AICD.