Suppressor of cytokine signaling 1 stringently regulates distinct functions of IL-7 and IL-15 in vivo during T lymphocyte development and homeostasis.
SOCS1(-/-) mice accumulate within the thymus and periphery CD8(+) lymphocytes that express memory cell markers and display heightened in vitro responses to common gamma-chain cytokines. To investigate whether dysregulated homeostasis of T lymphocytes and acquisition of memory phenotype by CD8(+) cells in SOCS1(-/-) mice were mediated by IL-7 and/or IL-15 in vivo, we have generated SOCS1(-/-)IL-7(-/-), SOCS1(-/-)IL-15(-/-) and SOCS1(-/-)IL-7(-/-)IL-15(-/-) mice. We observed that in mice lacking SOCS1, either IL-7 or IL-15 skewed thymocyte development toward CD8 lineage, whereas IL-15 is the principal mediator of dysregulated homeostasis in the periphery. Homeostatic proliferation of SOCS1(-/-) CD8(+) lymphocytes in Rag1(-/-), Rag1(-/-)IL-7(-/-), Rag1(-/-)IL-15(-/-), and Rag1(-/-)IL-7(-/-)IL-15(-/-) mice showed that SOCS1 deficiency did not overcome the requirement for IL-7 and IL-15 to sustain homeostatic expansion. Differential expression of memory phenotype markers CD44, CD122, and Ly6C by SOCS1(-/-)IL-15(-/-) CD8(+) lymphocytes suggest that multiple signals contributed to the memory cell differentiation program. To address whether increased IL-15 responsiveness of SOCS1(-/-) CD8(+) lymphocytes required prior TCR sensitization, we generated SOCS1(-/-) H-Y TCR transgenic (Tg) mice. Using female SOCS1(-/-) H-Y TCR(tg) mice in Rag1(+/+) and Rag1(-/-) backgrounds, we show that acquisition of the memory phenotype by SOCS1-deficient CD8(+) lymphocytes did not require prior antigenic stimulation, but required the presence of activated T cells. SOCS1 deficiency accelerated the maturation of CD8 single-positive thymocytes expressing Tg TCR, but did not compromise negative selection in HY-TCR(tg) males. Our findings illustrate distinct functions for IL-7 and IL-15 in T lymphocyte development and homeostasis, and stringent regulation of these processes by SOCS1.
Immunology Division, Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Canada.
Sheela
S
Ramanathan
Julien
J
Gagnon
Chantal
C
Leblanc
Robert
R
Rottapel
Subburaj
S
Ilangumaran
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006706:Homeostasis; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015851:Interleukin-7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development / Q000378:metabolism
D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D019409:Interleukin-15; D015851:Interleukin-7; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins