CD4 and CD8 are positive regulators of T cell receptor signal transduction in early T cell differentiation.
Although cortical (CD4+CD8+) thymocytes mobilize intracellular calcium poorly when CD3/TCR is ligated, we have found that murine cortical thymocytes can transduce strong biochemical signals in response to ligation of the CD3/Ti TCR complex (CD3/TCR) and that the signals are regulated by CD4 and CD8 interactions with CD3/TCR. Striking increases in intracellular calcium were observed in cortical thymocytes from transgenic mice containing productively rearranged alpha and beta TCR genes, when CD3 or TCR was cross-linked with CD4 or CD8 using heteroconjugated mAb. However, in mature T cells derived from lymph nodes of these mice, identical stimuli elicited calcium responses that were significantly smaller in magnitude. A thymocyte cell line that expresses a low level of the transgenic TCR and has a phenotype characteristic of cortical thymocytes (CD4+CD8+J11d+Thy-1+) was established from a female alpha beta TCR transgenic mouse. Cross-linking of CD4 or CD8 molecules to CD3/TCR induced strong calcium responses in these cells. Responses were weak or absent when CD3 or TCR were aggregated alone. Heteroconjugates of Thy-1xCD3 did not increase the intracellular calcium concentration in transgenic thymocytes or in the thymocyte cell line, although Thy-1 is highly expressed on immature cells. Enhanced tyrosine phosphorylation was observed when CD3 or TCR was cross-linked with CD4 or CD8 on transgenic thymocytes or on the thymocyte cell line, in comparison with aggregation of CD3/TCR alone. Taken together, these data show that CD4 and CD8 molecules allow the weakly expressed CD3/TCR of cortical thymocytes to transduce strong intracellular signals upon receptor ligation. These signals may be involved in selection processes at the CD4+CD8+ stage of differentiation.
Gilliland
L K
LK
Oncogen/Bristol-Myers Squibb, Seattle, WA 98121.
Teh
H S
HS
Uckun
F M
FM
Norris
N A
NA
Teh
S J
SJ
Schieven
G L
GL
Ledbetter
J A
JA
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D017252:CD3 Complex; D015704:CD4 Antigens / Q000502:physiology*; D016827:CD8 Antigens; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D003432:Cross-Linking Reagents; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019000:Phosphotyrosine; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D003432:Cross-Linking Reagents; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019000:Phosphotyrosine; D014443:Tyrosine; D002118:Calcium