CXCR6+ CD127– Tr1 cells balance immunity and persistence in Plasmodium falciparum infection
Jason Nideffer, Florian Bach, Steven Strubbe, Luis Lopez, Maato Zedi, Felistas Nankya, Jessica Briggs, Kattria van der Ploeg, Kenneth Musinguzi, Soyeon Kim, Aracely Garcia Romero, Arefin Keya, Kylie Camanag, Savannah Lewis, Muhammad Abdelbasset, Bing Wang, Allison Boss, Evelyn Nansubuga, Joaniter I. Nankabirwa, Emmanuel Arinaitwe, Saki Takahashi, Grant Dorsey, Bryan Greenhouse, Isabel Rodriguez-Barraquer, Moses R. Kamya, Rosa Bacchetta, Isaac Ssewanyana, Ashraful Haque, Maria Grazia Roncarolo, Prasanna Jagannathan
Jason Nideffer, Florian Bach, Steven Strubbe, Luis Lopez, Maato Zedi, Felistas Nankya, Jessica Briggs, Kattria van der Ploeg, Kenneth Musinguzi, Soyeon Kim, Aracely Garcia Romero, Arefin Keya, Kylie Camanag, Savannah Lewis, Muhammad Abdelbasset, Bing Wang, Allison Boss, Evelyn Nansubuga, Joaniter I. Nankabirwa, Emmanuel Arinaitwe, Saki Takahashi, Grant Dorsey, Bryan Greenhouse, Isabel Rodriguez-Barraquer, Moses R. Kamya, Rosa Bacchetta, Isaac Ssewanyana, Ashraful Haque, Maria Grazia Roncarolo, Prasanna Jagannathan
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Research Article Immunology Infectious disease

CXCR6+ CD127– Tr1 cells balance immunity and persistence in Plasmodium falciparum infection

Abstract

Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells capable of long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical knowledge gap, we first performed scRNA-seq on gated cell populations and validated CXCR6+ CD127– as new phenotypic markers to enrich for bona fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127– Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFN-γ during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFN-γ, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127– Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

Authors

Jason Nideffer, Florian Bach, Steven Strubbe, Luis Lopez, Maato Zedi, Felistas Nankya, Jessica Briggs, Kattria van der Ploeg, Kenneth Musinguzi, Soyeon Kim, Aracely Garcia Romero, Arefin Keya, Kylie Camanag, Savannah Lewis, Muhammad Abdelbasset, Bing Wang, Allison Boss, Evelyn Nansubuga, Joaniter I. Nankabirwa, Emmanuel Arinaitwe, Saki Takahashi, Grant Dorsey, Bryan Greenhouse, Isabel Rodriguez-Barraquer, Moses R. Kamya, Rosa Bacchetta, Isaac Ssewanyana, Ashraful Haque, Maria Grazia Roncarolo, Prasanna Jagannathan

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Figure 4

Cytokine production by memory CD4+ T cell subsets following stimulation.

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Cytokine production by memory CD4+ T cell subsets following stimulation....
(A) Longitudinal sampling and experimental timeline depicting how samples were provided by children and adults from Uganda enrolled in MUSICAL. Sampling occurred in the context of symptomatic and asymptomatic infections experienced by the same individual. Plasma and PBMCs derived from the same blood sample were analyzed by flow cytometry and NULISA, respectively. (B) Histogram depicting the ages (at diagnosis) of children followed in this study. Timepoints from symptomatic and asymptomatic infections are included for each individual. Lines represent smoothed average counts. (C–F) The percentage of memory CD4+ T cells that belonged to a given subset (defined by surface markers) and produced IL-10 (C and D) or IFN-γ (E and F) in response to stimulation with PMA and ionomycin (C and E) or in response to iRBC stimulation (D and F). (G and H) The percentage of CXCR5+ PD-1+ cTfh or cytokine-expressing (G, IL-10; H, IFN-γ) CXCR5+ PD-1+ cTfh that were also CXCR6+ CD127– (stimulated with iRBCs). (I and J) The percentage of CXCR6+ CD127– Tr1 cells and cytokine-expressing (I, IL-10; J, IFN-γ) CXCR6+ CD127– Tr1 cells that were also CXCR5+ PD-1+. For single comparisons, significance was determined via paired T tests. For, multiple pair-wise comparisons (C–F), significance was determined using a Wald test (including study participant as a random intercept) followed by P value adjustment using the Benjamini-Hochberg false discovery rate (FDR) procedure. All significant comparisons are annotated; **P < 0.01; ***P < 0.001. For all plots, data points represent an aggregate of measurements from a single MUSICAL participant sampled at multiple timepoints before, during, and after symptomatic and asymptomatic infections.