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CD4+Foxp3+regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREGcells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREGcell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREGcells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREGcells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREGcells. In the absence of ST2, TREGcells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+TREGover pro-inflammatory TREGcells in a Cryptococcus neoformansinfection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREGcells, ultimately dictating the dynamics of adaptive immunity to pathogens.

CD4+Foxp3+regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREGcells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREGcell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREGcells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREGcells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREGcells. In the absence of ST2, TREGcells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+TREGover pro-inflammatory TREGcells in a Cryptococcus neoformansinfection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREGcells, ultimately dictating the dynamics of adaptive immunity to pathogens.

ABSTRACTThe genetic basis of natural susceptibility to progressive Cryptococcus neoformansinfection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformanssusceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2mice 35 days after C. neoformansinfection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b+dendritic cells, and CD4+cells in B6.CBA-Cnes2than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2mice. Taken together, these findings demonstrate that the Cnes2interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformansinfection.

Johnson: Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding.

Background:Immune checkpoint (IC) blockade has revolutionized the treatment of chemo-refractory solid tumors and has demonstrated promising results for the treatment of resistant blood cancers, including lymphoma. However, clinical response to PD1 blockade depends on the subtype of lymphoma, with durable responses observed in 70 % of Hodgkin lymphoma (HL) patients versus only 36 to 40% of Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) patients(1-3). The biological aspects that hinder the efficacy of immunotherapy in DLBCL and FL patient are not well-known. Primary tumor resistance to PD1 blockade could be driven by inherent genomic alterations or by ineffective anti-tumor T cell responses. ICs expressed at the surface of tumor-infiltrating-lymphocytes (TILs) use distinct suppressive mechanisms to enforce T-cell dysfunction. The collective expression of ICs defines multiple subsets of exhausted T cells during cancer(4). Since multiple of these ICs collaborate to repress anti-tumor T cell functions, we hypothesized that TILs from DLBCL and FL patients express high levels of ICs and present a more advanced exhausted phenotype compared to TILs from HL patients.