Molecular interactions, T-cell subsets and a role of the CD4/CD8:p56lck complex in human T-cell activation.
Several T-cell structures are capable of generating intracellular signals linked to T-cell proliferation. Crosslinking of CD2, CD4 and CD45 with Ti/CD3 to several of these antigens can augment the minimal signal induced by antigen binding to the Ti/CD3 complex. Importantly, some of these regulatory structures (CD4, CD8 and CD45) are also expressed on subsets of T cells with distinct activation requirements and functional programs (helper, suppressor, suppressor-inducer and cytotoxic function). The CD4+ CD45RA+ (2H4+) subset responds well to self-Ia, poorly to soluble antigen and possesses suppressor-inducer function. A reciprocal subset CD4+ CD45RA- (4B4+) is preferentially activated by soluble recall antigens and possesses helper function. Each of these subsets can be distinguished by virtue of the differential expression of CD45 antigens. Importantly, the anti-2H4 antibody which reacts with a specific region near the N-terminus of two CD45 isoforms can effectively block its function. Crosslinking of CD4 with the Ti/CD3 complex preferentially activated the CD4+ CD45+ RA- subset, while soluble antibodies to CD2 preferentially affected the CD45 CD45RA+ subset. Thus, CD3 and CD4 more effectively synergize in the activation process on the CD4+ CD45RA- subset, a result consistent with the ability of this subpopulation to respond to recall antigens. The regulatory role of the CD4, CD8 and CD45 antigens may be mediated by an interactive network of protein-tyrosine phosphorylation and dephosphorylation. We have shown the CD4 and CD8 antigens to be associated with the T cell-specific protein-tyrosine kinase (p56lck). p56lck is a member of a family of protein-tyrosine kinases with an established ability to activate and transform mammalian cells. The CD4/CD8:p56lck complex is catalytically active as shown by its ability to phosphorylate various members of the Ti/CD3 complex. By contrast, the CD45 antigens possess protein-tyrosine phosphatase activity within their intracellular domains and are postulated to function by virtue of a regulatory interaction with CD4/CD8:p56lck and its potential substrates. Thus, the differences in the response of the CD4+ CD45RA+/- subsets to various stimuli and the expansion of T-cell subsets with distinct immunoregulatory programs may be governed by a pathway of tyrosine-mediated events.
Rudd
C E
CE
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA.
Anderson
P
P
Morimoto
C
C
Streuli
M
M
Schlossman
S F
SF
D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000502:physiology; D000954:Antigens, Surface / Q000276:immunology / Q000502:physiology; D017252:CD3 Complex; D015704:CD4 Antigens / Q000276:immunology / Q000502:physiology; D016827:CD8 Antigens; D006801:Humans; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)