Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function.
Active suppression by T regulatory (Tr) cells plays an important role in the downregulation of T cell responses to foreign and self-antigens. Mouse CD4(+) Tr cells that express CD25 possess remarkable suppressive activity in vitro and in autoimmune disease models in vivo. Thus far, the existence of a similar subset of CD25(+)CD4(+) Tr cells in humans has not been reported. Here we show that human CD25(+)CD4(+) Tr cells isolated from peripheral blood failed to proliferate and displayed reduced expression of CD40 ligand (CD40L), in response to T cell receptor-mediated polyclonal activation, but strongly upregulated cytotoxic T lymphocyte-associated antigen (CTLA)-4. Human CD25(+)CD4(+) Tr cells also did not proliferate in response to allogeneic antigen-presenting cells, but they produced interleukin (IL)-10, transforming growth factor (TGF)-beta, low levels of interferon (IFN)-gamma, and no IL-4 or IL-2. Importantly, CD25(+)CD4(+) Tr cells strongly inhibited the proliferative responses of both naive and memory CD4(+) T cells to alloantigens, but neither IL-10, TGF-beta, nor CTLA-4 seemed to be directly required for their suppressive effects. CD25(+)CD4(+) Tr cells could be expanded in vitro in the presence of IL-2 and allogeneic feeder cells and maintained their suppressive capacities. These findings that CD25(+)CD4(+) Tr cells with immunosuppressive effects can be isolated from peripheral blood and expanded in vitro without loss of function represent a major advance towards the therapeutic use of these cells in T cell-mediated diseases.
Levings
M K
MK
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, Milan, Italy 20132.
Sangregorio
R
R
Roncarolo
M G
MG
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis*; D060908:CTLA-4 Antigen; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D018796:Immunoconjugates; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007519:Isoantigens; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000069594:Abatacept