The SLAM-associated protein signaling pathway is required for development of CD4+ T cells selected by homotypic thymocyte interaction.
MHC class II-expressing double-positive thymocytes induce progression of CD4(+) T cell development as efficiently as cortical thymic epithelial cells do. Because double-positive thymocytes expressing CD1d select natural killer T (NKT) cells, we investigated whether thymocyte-selected CD4(+) (T-CD4) T cells require the same signaling components as NKT cells. Using bone-marrow chimeras, we found that the signaling molecules SAP, Fyn, and PKCtheta were essential for T-CD4 T cell generation, whereas mutations in the Ly108 receptor, interleukin-15 receptor alpha, or the transcription factor T-bet had a marginal effect. Furthermore, SAP was critical for IL-4 production by T-CD4 T cells, but the PKCtheta deficiency did not alter the ability of T-CD4 T cells to produce cytokines. T-bet was necessary to produce the maximum amount of IFN-gamma for CD4(+) T cells regardless of the selection pathway. Thus, in contrast to epithelial cell-selected CD4(+) T cells, the two distinct lineages of T cells selected by thymocytes--i.e., T-CD4 and NKT cells--both utilize the SAP-Fyn-PKCtheta pathway for their development and function.
Li
Wei
W
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. wl1@iupui.edu
Sofi
M Hanief
MH
Rietdijk
Svend
S
Wang
Ninghai
N
Terhorst
Cox
C
Chang
Cheong-Hee
CH
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018183:Transplantation Chimera
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D011493:Protein Kinase C