CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell-produced IL-2.
CD4+CD25+ regulatory T cells (T reg) development and homeostasis require IL-2 and costimulation through same TNF-receptor family members. CD40KO mice have reduced number of T reg in peripheral blood, thymus and spleen. Herein we show that naive T reg express low basal level of CD40L that is upregulated upon TCR-triggered mediated activation. Treatment of wt mice with Ab blocking CD40/CD40L interaction results in a fast decrease in T reg number that rapidly recovers upon Ab withdrawal. CFSE-labeled T reg from wt mice injected into CD40KO, but not wild-type (wt) mice, showed reduced survival and proliferation in homeostatic setting. In vitro, dendritic cells from CD40KO mice but not wt mice produce diminished amount of IL-2 upon T reg encounter and are impaired in expanding T reg, a defect corrected by the addition of rIL-2. Accordingly, four daily IL-2 administrations to CD40KO mice normalize T reg number by promoting both their survival and homeostatic proliferation. Such IL-2 effect is transient since T reg number returns to the low constitutive level described in CD40KO mice within 5 days upon IL-2 withdrawal thus suggesting that IL-2 is persistently needed to assure T reg homeostasis.
Guiducci
Cristiana
C
Immunotherapy and Gene Therapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Valzasina
Barbara
B
Dislich
Heidrun
H
Colombo
Mario P
MP
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology / Q000502:physiology; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D019013:CD40 Antigens; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand