Defective T cell development and function in the absence of Abelson kinases.
Thymocyte proliferation, survival, and differentiation are tightly controlled by signaling from the pre-TCR. In this study, we show for the first time that the Abelson (Abl) kinases regulate proximal signaling downstream of the pre-TCR. Conditional deletion of Abl kinases in thymocytes reveals a cell-autonomous role for these proteins in T cell development. The conditional knockout mice have reduced numbers of thymocytes, exhibit an increase in the percentage of the CD4(-)CD8(-) double-negative population, and are partially blocked in the transition to the CD4(+)CD8(+) double-positive stage. Moreover, the total number of T cells is greatly reduced in the Abl mutant mice, and the null T cells exhibit impaired TCR-induced signaling, proliferation, and cytokine production. Notably, Abl mutant mice are compromised in their ability to produce IFN-positive CD8 T cells and exhibit impaired CD8(+) T cell expansion in vivo upon Listeria monocytogenes infection. Furthermore, Ab production in response to T cell-dependent Ag is severely impaired in the Abl mutant mice. Together these findings reveal cell-autonomous roles for the Abl family kinases in both T cell development and mature T cell function, and show that loss of these kinases specifically in T cells results in compromised immunity.
Gu
Jing Jin
JJ
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Zhang
Nu
N
He
You-Wen
YW
Koleske
Anthony J
AJ
Pendergast
Ann Marie
AM
D000818:Animals; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D018390:Gene Targeting; D000068877:Imatinib Mesylate; D007154:Immune System Diseases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D001549:Benzamides; D016207:Cytokines; D010879:Piperazines; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl