title: IL-2 promotes the function of memory-like autoregulatory CD8+ T cells but suppresses their development via FoxP3+ Treg cells.
abstract: IL-2 plays a critical role in both effector T-cell development and FoxP3(+) CD4(+)  Treg-cell homeostasis. A reduction in Il2 transcription results in impaired FoxP3(+) CD4(+)  Treg-cell recruitment and function, and accounts for the association between murine Il2 and type 1 diabetes (T1D). The progression of T1D elicits a disease-countering negative feedback regulatory loop that involves the differentiation of low-avidity autoreactive CD8(+)  T cells into memory-like autoregulatory T cells in a CD4(+)  Th-dependent manner. Since these auto-regulatory T cells express IL-2Rβ (CD122), we hypothesized that their development might also be regulated by IL-2. Here, we investigate the effects of differences in IL-2 expression on this autoregulatory subset. We show that decreased IL-2 production impairs the regulatory capacity of memory-like autoregulatory CD8(+) CD122(+)  T cells. Surprisingly, we also find that a reduction in IL-2 production capacity increases memory autoregulatory CD8(+)  T-cell formation indirectly, by decreasing the development and function of FoxP3(+)  Treg cells in nonobese diabetic mice. These results illustrate a complex homeostatic interplay between IL-2, CD4(+)  Th cells, FoxP3(+) CD4(+)  Treg cells and autoregulatory CD8(+)  T-cell memory whereby IL-2 controls the function of both Treg-cell subsets, but IL-2-potentiation of FoxP3(+) CD4(+)  Treg-cell function results in the suppression of CD4(+)  Th-cell activation and autoregulatory memory CD8(+)  T-cell formation.
authors.affiliation: Julia McFarlane Diabetes Research Centre and Departments of Microbiology, Snyder Institute for Chronic Diseases, the University of Calgary, Calgary, AB, Canada.
authors.forename: Afshin
authors.initials: A
authors.lastname: Shameli
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.forename: Sue
authors.initials: S
authors.lastname: Tsai
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Xavier
authors.initials: X
authors.lastname: Clemente-Casares
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508022:Il2rb protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D011948:Receptors, Antigen, T-Cell