PD-1 modulates the expansion of Th1/Th17 populations during active tuberculosis

JURADO JO; ALVAREZ IB; PEÑA D; ROVETTA AI; HERNÁNDEZ DEL PINO RE; CASTAGNINO J; MUSELLA RM; PASQUINELLI V; GARCÍA VE

CAPITAL FEDERAL

Congreso; First French-Argentine Immunology Congress (FAIC); 2010

An appropriate immune response against M. tuberculosis (Mtb) requires Th1 cytokine responses; in particular, IFN-γ. However, although this cytokine displays a crucial role, its secretion is not enough to achieve a complete protection against the pathogen. Accordingly, it was shown that IL-17 produced by CD4 T cells would be required to eliminate primary infection. Besides the existence of Th1 and Th17 populations, another subset of CD4+IFN-γ+IL-17+ cells was described. Thus, here we analyzed the role of CD4+ cells during active tuberculosis (TB). Stimulation of PBMC with the specific Ag (Mtb) induced significantly higher levels of IL-17 from TB patients compared to healthy donors (HD) (TB: 414±79pg/ml; HD: 276±45pg/ml; p>0.01). Moreover, Mtb induced a striking increment in CD4+IL-17+ cells as well (TB: 9±1%; HD: 5±1%; p>0.01). Interestingly, more than 60% of IL-17 producing cells were IFN-γ+ (TB: 62±5%, HD: 64±4%), suggesting the existence of a Th1/Th17 population that secrete IL-17 in response to Mtb. However, the proportions of each population vary significantly, given that in HD to 75% of the cells are IFN-γ+IL-17-, 16% IFN-γ+IL-17+ and 9% IFN-γ-IL-17+, whereas in TB we found, 55%, 29% and 16% respectively. Previously we demonstrated that PD-1 inhibits Th1 responses in TB. Then, we studied the expression and function of PD-1 on Th17 cells. We found that Mtb stimulation induced PD-1 expression on more than 90% of CD4+IL-17+ cells. Furthermore, by blocking the PD-1 pathway we observed a significant increase in IL-17 production (Mtb: 420±56pg/ml; Mtb+PD-1: 795± 56pg/ml) and in the number of CD4+IL-17+ cells as well (Mtb: 10±1%, Mtb+PD-1: 15±1%). However, PD-1 blockage did not modify IL-17 mean intensity fluorescence, indicating that PD-1 would inhibit the expansion of Th17 cells. Then, our data demonstrated the simultaneous presence of Th1 and Th17 cells to fight Mtb. Furthermore, Th1 and Th17 populations would be modulated by the same pathways during active TB.t