Inhibition of T cell proliferation by cholera toxin involves the modulation of costimulatory molecules CTLA-4 and CD28.
Cholera toxin (CT) is known to inhibit the proliferation of murine and human T lymphocytes. In this study we have analysed the mechanisms underlying the inhibitory effect of CT on subpopulations of human CD4+ and CD8+ T lymphocytes. We show that CT dramatically prevents the activation of resting T lymphocytes, whereas it has a minor effect on cells that have been previously activated. Analysis of DNA content of the CT-treated T cells showed an arrest in the G(0)/G(1) phase and this correlated with high expression of the cyclin-dependent kinase inhibitor p27(kip). Moreover, we show that CT up-regulates the expression of the inhibitory molecule CTLA-4 in naïve, effector and memory resting CD4+ T cells and in resting CD8+ T lymphocytes. The regulation of CTLA-4 expression by CT is at the transcriptional level. Indeed, in cells treated with CT we observed an increase of two mRNA variants coding for the membrane and the soluble CTLA-4 molecules. In parallel with the up-regulation of the inhibitory CTLA-4, CT down-modulates the costimulatory molecule CD28 on CD4+ and CD8+ resting T cells. The increased expression of CTLA-4 played a role in controlling T cell activation and function as blocking anti-CTLA-4 F(ab')(2) mAbs partially inhibited anti-CD3 mAbs induced proliferation. These findings show that the inhibition of T cell proliferation by CT affects early stages of the T cell activation and involves the modulation of costimulatory molecules CTLA-4 and CD28 on resting T cells.
Vendetti
Silvia
S
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy. vendetti@iss.it
Riccomi
Antonella
A
Sacchi
Alessandra
A
Sciaraffia
Ester
E
Gatta
Lucia
L
Pioli
Claudio
C
De Magistris
Maria Teresa
MT
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002453:Cell Cycle; D049109:Cell Proliferation; D002772:Cholera Toxin / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D002772:Cholera Toxin