Impaired survival and proliferation in IL-7 receptor-deficient peripheral T cells.
Mice genetically deficient in IL-7R(alpha) are highly lymphopenic in the peripheral lymphoid organs. The functional competence of T cells that have developed in the absence of an IL-7R signal was investigated. Three important observations were made using several in vitro activation regimens. First, stimulation of T cells from IL-7R -/- mice at limiting dilution with immobilized Abs to CD3, CD4 or CD8, and CD18 revealed a six- to sevenfold reduction in the frequency of clonogenic T cells compared with T cells from IL-7R +/+ mice. IL-7R -/- T cells were also significantly less responsive to alloantigen as well as to receptor-independent stimuli such as PMA and ionomycin. Furthermore, the average clone size of single IL-7R -/- T cells was 50% smaller than that of IL-7R +/+ T cells. These data suggest that the reduced clonogenicity was predominantly due to intrinsic deficiencies in the ability of IL-7R -/- T cells to proliferate upon stimulation. Second, analysis of the kinetics of cell growth of IL-7R -/- T cells revealed that a significant proportion of T cells failed to proliferate within the first 72 h of in vitro stimulation, with the majority undergoing programmed cell death. Third, both clonogenic IL-7 -/- T cells and IL-7R +/+ T cells showed a similar proliferative response in the presence of IL-2 and similar survival kinetics, indicating that a subpopulation of IL-7R -/- T cells is functionally mature. We propose that an absence of IL-7R signaling not only affects T cell development in the thymus, but also results in the accumulation of functionally inactive T cells in the periphery.
Maraskovsky
E
E
Department of Cellular Immunology, Immunex Corporation, Seattle, WA 98101, USA.
Teepe
M
M
Morrissey
P J
PJ
Braddy
S
S
Miller
R E
RE
Lynch
D H
DH
Peschon
J J
JJ
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018123:Receptors, Interleukin / Q000502:physiology*; D020395:Receptors, Interleukin-7; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology; D019014:fas Receptor / Q000276:immunology
D015703:Antigens, CD; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D019014:fas Receptor