Cholecystokinin octapeptide regulates the differentiation and effector cytokine production of CD4+ T cells in vitro

• CCK-8 inhibits Th1 cell polarization from CD4+ T cells.
• CCK-8 inhibits Th17 cell differentiation and promotes Treg cell generation.
• CCK-8 regulates the expression of transcription factors and signature cytokines.
• CCK-8 regulates effector cytokine secretion.
• The effect of CCK-8 on CD4+ T cell differentiation is mainly mediated by CCK2R.

Cholecystokinin octapeptide (CCK-8), an immunomodulatory peptide, can promote or suppress the development or function of specific CD4+ T cell subsets by regulating antigen-presenting cell functions. In the current study, we investigated whether CCK-8 exerts a direct effect on T cells through influencing differentiation and cytokine production of distinct CD4+ T cell subsets in vitro. Our results showed that CCK-8 differentially affects the development and function of CD4+ T cell populations, with a negative influence on Th1 and Th17 cells and positive regulatory effect on inducible T regulatory cells (iTreg). Notably, CCK-8 suppressed Th1 while slightly enhancing Th2 development and cytokine production. Similarly, CCK-8 inhibited the differentiation of Th17 cells and promoted Foxp3 expression. L-364,718 and LY-288,513, selective antagonists of CCK1R and CCK2R, respectively, suppressed the effects of CCK-8 on CD4+ T cell subset-specific transcription factors. Our findings strongly indicate that CCK-8 exerts a direct effect on T cells, which is dependent on CCKRs, particularly CCK2R. The collective results aid in further clarifying the mechanism underlying the anti-inflammatory and immunoregulatory effects of CCK-8.