Abnormal T cell development in CD3-zeta-/- mutant mice and identification of a novel T cell population in the intestine.
The T cell antigen receptor (TCR)-associated invariable membrane proteins (CD3-gamma, -delta, -epsilon and -zeta) are critical to the assembly and cell surface expression of the TCR/CD3 complex and to signal transduction upon engagement of TCR with antigen. Disruption of the CD3-zeta gene by homologous recombination resulted in a structurally abnormal thymus which primarily contained CD4- CD8- and TCR/CD3very lowCD4+CD8+ cells. Spleen and lymph nodes of CD3-zeta-/- mutant mice contained a normal number and ratio of CD4+ and CD8+ single positive cells that were TCR/CD3very low. These splenocytes did not respond to antibody cross-linking or mitogenic triggering. The V beta genes of CD4-CD8- and CD4+CD8+ thymocytes and splenic T cells were productively rearranged. These data demonstrated that (i) in the absence of the CD3-zeta chain, the CD4- CD8- thymocytes could differentiate to CD4+CD8+ TCR/CD3very low thymocytes, (ii) that thymic selection might have occurred, (iii) but that the transition to CD4+CD8- and CD4-CD8+ cells took place at a very low rate. Most strikingly, intraepithelial lymphocytes (IELs) isolated from the small intestine or the colon expressed normal levels of TCR/CD3 complexes on their surface which contained Fc epsilon RI gamma homodimers. In contrast to CD3-zeta containing IELs, these cells failed to proliferate after triggering with antibody cross-linking or mitogen. In comparison to thymus-derived peripheral T cells in the spleen and lymph nodes, the preferential expression of normal levels of TCR/CD3 in intestinal IELs suggested they mature via an independent extrathymic pathway.
Liu
C P
CP
Division of Immunology, Beth Israel Hospital/Harvard Medical School, Boston, MA 02215.
Ueda
R
R
She
J
J
Sancho
J
J
Wang
B
B
Weddell
G
G
Loring
J
J
Kurahara
C
C
Dudley
E C
EC
Hayday
A
A
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D017252:CD3 Complex / Q000235:genetics*; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D005434:Flow Cytometry; D007422:Intestines / Q000166:cytology*; D007694:Killer Cells, Natural / Q000166:cytology; D008198:Lymph Nodes / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain