Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients.
The present study demonstrates that CD4(+)CD25(+) T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4(+)CD25(+) T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4(+)CD25(+) T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4(+)CD25(-) T cells, CD4(+)CD25(+) T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4(+)CD25(+) T cells. Furthermore, addition of increasing numbers of CD4(+)CD25(+) T cells resulted in a dose-dependent inhibition of CD4(+)CD25(-) T-cell proliferation to tuberculin and p24. CD4(+)CD25(+) T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor beta (TGF-beta) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4(+) T cells among the CD4(+)CD25(+) T-cell subset. Suppressive activity was not dependent on the secretion of TGF-beta or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4(+)CD25(+) regulatory T cells, which might induce a tolerance to HIV in vivo.
Weiss
Laurence
L
Institut National de la Santé et de la Recherche Médicale U430, University of Paris V, France. laurence.weiss@egp.ap-hop-paris.fr.
Donkova-Petrini
Vladimira
V
Caccavelli
Laure
L
Balbo
Michèle
M
Carbonneil
Cédric
C
Levy
Yves
Y
D023241:Antiretroviral Therapy, Highly Active; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002455:Cell Division / Q000276:immunology; D000939:Epitopes; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015704:CD4 Antigens; D000939:Epitopes; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10