Polyfunctional and IFN-γ monofunctional human CD4+ T cell populations are molecularly distinct
Julie G. Burel, Simon H. Apte, Penny L. Groves, James S. McCarthy, Denise L. Doolan
Julie G. Burel, Simon H. Apte, Penny L. Groves, James S. McCarthy, Denise L. Doolan
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Research Article Cell biology

Polyfunctional and IFN-γ monofunctional human CD4+ T cell populations are molecularly distinct

Abstract

Pathogen-specific polyfunctional T cell responses have been associated with favorable clinical outcomes, but it is not known whether molecular differences exist between polyfunctional and monofunctional cytokine-producing T cells. Here, we report that polyfunctional CD4+ T cells induced during Plasmodium falciparum (P. falciparum) blood-stage infection in humans have a unique transcriptomic profile compared with IFN-γ monofunctional CD4+ T cells and, thus, are molecularly distinct. The 14-gene signature revealed in P. falciparum–reactive polyfunctional T cells is associated with cytokine signaling and lymphocyte chemotaxis, and systems biology analysis identified IL-27 as an upstream regulator of the polyfunctional gene signature. Importantly, the polyfunctional gene signature is largely conserved in Influenza-reactive polyfunctional CD4+ T cells, suggesting that polyfunctional T cells have core characteristics independent of pathogen specificity. This study provides the first evidence to our knowledge that consistent molecular differences exist between polyfunctional and monofunctional CD4+ T cells.

Authors

Julie G. Burel, Simon H. Apte, Penny L. Groves, James S. McCarthy, Denise L. Doolan

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Figure 3

Phenotypic differences in P. falciparum–reactive polyfunctional and monofunctional CD4+ T cells induced during P. falciparum blood-stage experimental infection in malaria-naive volunteers.

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Phenotypic differences in P. falciparum–reactive polyfunctional and mono...
Cytokine production in CD4+ T cells was measured by flow cytometry and intracellular cytokine staining after in vitro stimulation of whole blood samples with Pf prbc parasite antigen extract overnight. (A) Comparison of the mean fluorescence intensities for cytokines IFN-γ, IL-2, or TNF-α between triple positive (3+) and IFN-γ single positive (IFN-γ 1+), IL-2 single positive (IL-2 1+), or TNF-α single positive (TNF-α 1+) CD4+ T cells, respectively, matched by volunteers. (B) KLRG1 expression in triple positive (3+) and IFN-γ, IL-2, or TNF single positive (1+) CD4+ T cells circulating 4 weeks after infection. Data represent mean from (A) 19 volunteers from 3 independent cohorts and (B) 8 volunteers from 2 independent cohorts. ****P < 0.0001 (Wilcoxon test). Error bars indicate ±SD.