SEQUESTRATION OF CD4-ASSOCIATED LCK FROM THE TCR COMPLEX MAY ELICIT T-CELL HYPORESPONSIVENESS IN NONOBESE DIABETIC MICE

The Lck protein tyrosine kinase associates noncovalently with the cyto plasmic domain of CD4. Upon ligand engagement of the TCR, CD4-associat ed Lck is rapidly activated and recruited to the TCR complex, Coupling of this complex to an intracellular signaling pathway mag. result in T cell proliferation, Previously, we reported that thymocytes from non obese diabetic (NOD) mice (greater than or equal to 6 wk of age) exhib it a proliferative hyporesponsiveness after TCR stimulation, which is associated with defective TCR-mediated signaling along the protein kin ase C/Ras/mitogen-activated protein kinase pathway of T cell activatio n, Here, we investigated whether differential association of Lck with TCR or CD4 mediates the control of NOD thymocyte hyporesponsiveness. W e demonstrate that less CD4-associated Lck is recruited to the TCR in activated NOD thymocytes than in control thymocytes. This CD4-mediated sequestration of Lck from the TCR correlates with the increased bindi ng of CD4-associated Lck through its Src homology 2 domain to free TCR zeta and CD3 gamma epsilon chains on the plasma membrane, Sequestrati on of Lck by CD4 does not occur in activated thymocytes from 3-wk-old NOD mire and is only apparent in thymocytes from NOD mice >5 to 6 wk o f age, This diminished recruitment of CD4-associated Lck to the TCR is not mediated by an increase in the amount of CD4-associated Lck, Thus , impaired recruitment of CD3-associated Lck to the TCR complex may re present an early event that results in deficient coupling of the TCR c omplex to downstream signaling events and gives rise to NOD thymocyte hyporesponsiveness.