PTPN2 attenuates T-cell lymphopenia-induced proliferation.
When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8(+) T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigen-experienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptor-dependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Florian
F
Wiede
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
Nicole L
NL
La Gruta
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Tony
T
Tiganis
D000818:Animals; D015551:Autoimmunity / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology; D066298:In Vitro Techniques; D015851:Interleukin-7 / Q000502:physiology; D008231:Lymphopenia / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000172:deficiency / Q000502:physiology*; D011830:Radiation Effects; D013950:Thymus Gland / Q000473:pathology
D015851:Interleukin-7; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516653:Ptpn2 protein, mouse