ShcA regulates late stages of T cell development and peripheral CD4⁺ T cell numbers

T cell development in the thymus is a highly regulated process that critically depends upon productive signaling via the preTCR at the β-selection stage, as well as via the TCR for selection from the CD4⁺CD8⁺ double-positive stage to the CD4 or CD8 singlepositive stage. ShcA is an adapter protein expressed in thymocytes, and it is required for productive signaling through the preTCR, with impaired signaling via ShcA leading to a developmental block at the β-selection checkpoint. However, the role of ShcA in subsequent stages of T cell development has not been addressed. In this study, we generated transgenic mice (CD4-Cre/ShcFFF mice) that specifically express a phosphorylation-defective dominant-negative ShcA mutant (ShcFFF) in late T cell development. Thymocytes in CD4-Cre/ShcFFF mice progressed normally through the β-selection checkpoint, but displayed a significant reduction in the numbers of single-positive CD4⁺ and CD8⁺ thymocytes. Furthermore, CD4-Cre/ShcFFF mice, when bred with transgenic TCR mouse strains, had impaired signaling through the transgenic TCRs. Consistent with defective progression to the single-positive stage, CD4-Cre/ShcFFF mice also had significant peripheral lymphopenia. Moreover, these CD4-Cre/ShcFFF mice develop attenuated disease in CD4⁺ T cell-dependent experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Collectively, these data identify an important role for the adapter protein ShcA in later stages of thymic T cell development and in peripheral T cell-dependent events.