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 cytoplasmic domain of CD4. Upon ligand engagement of the TCR, CD4-associated Lck is rapidly activated and recruited to the TCR complex. Coupling of this complex to an intracellular signaling pathway may result in T cell proliferation. Previously, we reported that thymocytes from nonobese diabetic (NOD) mice (> or = 6 wk of age) exhibit a proliferative hyporesponsiveness after TCR stimulation, which is associated with defective TCR-mediated signaling along the protein kinase C/Ras/mitogen-activated protein kinase pathway of T cell activation. Here, we investigated whether differential association of Lck with TCR or CD4 mediates the control of NOD thymocyte hyporesponsiveness. We 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 binding of CD4-associated Lck through its Src homology 2 domain to free TCRzeta and CD3gamma epsilon chains on the plasma membrane. Sequestration of Lck by CD4 does not occur in activated thymocytes from 3-wk-old NOD mice and is only apparent in thymocytes from NOD mice >5 to 6 wk of age. This diminished recruitment of CD4-associated Lck to the TCR is not mediated by an increase in the amount of CD8-associated Lck. Thus, impaired recruitment of CD4-associated Lck to the TCR complex may represent an early event that results in deficient coupling of the TCR complex to downstream signaling events and gives rise to NOD thymocyte hyporesponsiveness.
Zhang
J
J
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.
Salojin
K
K
Delovitch
T L
TL
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D005260:Female; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011485:Protein Binding / Q000276:immunology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D018909:src Homology Domains / Q000276:immunology
D015704:CD4 Antigens; D008565:Membrane Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D016692:Receptors, Antigen, T-Cell, gamma-delta; C061836:antigen T cell receptor, epsilon chain; C054979:antigen T cell receptor, zeta chain; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)