Eleonora Sala

Conference 2023 Live Talk

Talk title

Interferon gamma suppresses T follicular helper cell and antibody responses upon viral infection

Authors and Affiliations

Eleonora Sala1,2, Marta Mangione1,2, Chiara Laura1,2,3, Maria Nelli1,2, Eleonora Consolo1,2, Cristian Gabriel Beccaria1,2, Matteo Iannacone1,2*, and Mirela Kuka1,2*

1. Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
2. Vita-Salute San Raffaele University, 20132 Milan, Italy

Abstract

Background

Although humoral and cellular immunity upon viral infections usually co-exist, sometimes one of the two responses emerges as dominant and is responsible for most of the antiviral activity. For example, vesicular stomatitis virus (VSV) infection induces early and potent neutralizing antibody (nAb) responses, whereas lymphocytic choriomeningitis virus (LCMV) infection induces strong cellular responses, but weak nAb responses. Recent work from our laboratory has shown that unbalance is observed also at the level of CD4 T cells responses, with subcutaneous VSV infection inducing strong TFH polarization that supports nAb responses, and subcutaneous LCMV in contrast promoting an extreme TH1 differentiation with no TFH.

Methods

To investigate the transcriptional heterogeneity of CD4+ T cell differentiation in the context of subcutaneous LCMV infection we performed single-cell RNA sequencing (scRNA-seq). We then systematically address the role of IFN gamma taking advantage of IFN gamma neutralizing antibodies and we assessed CD4+ T cell and B cell activation at the peak of adaptive immune responses via flow cytometry. B cell responses were analyzed by antibodies production. Finally, we employed confocal microscopy to study the localization of CD4+ T cells and B cells within the secondary lymphoid organs.

Results

Single-cell RNA sequencing revealed that LCMV-specific TH1 cells comprise at least to distinct subsets, one of which expresses TCF1, which is usually expressed by TFH. We found that blocking of IFN gamma results in the transition of this atypical T-bet+ TCF1+ cells into TFH cells, and in an increased number of germinal center B cells and antibodies.

Conclusions

Our results identify IFN gamma as a molecular switch that suppresses TFH and antibody responses while supporting TH1 differentiation upon viral infection. This might be an additional mechanism whereby viruses like LCMV interfere with the generation of efficient antibody responses.