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Science Immunology  04 Oct 2019:
Vol. 4, Issue 40, eaaz6073
DOI: 10.1126/sciimmunol.aaz6073

Abstract

T follicular regulatory cells restrain and refine germinal center responses in vivo.

B cells rely on T follicular helper cells (TFH) to direct antibody responses within germinal centers, but it is currently unknown how these responses are finely tuned. Although the ability of T follicular regulatory cells (TFR) to suppress B cell responses in vitro has been demonstrated, their role in germinal centers in vivo is less certain. Clement et al. have developed a TFR-deleter mouse to precisely quantify the temporal regulation of B cell responses during the development of the germinal center response. Deletion of TFR during early but not late germinal center development significantly increased plasma cell frequencies and antigen-specific immunoglobulin G (IgG) responses. Consequently, antibody memory responses also surged when TFR were deleted in the early germinal center, and the affinity of these antibodies was reduced, indicating that TFR may play a critical role in fine tuning antibody selection and the magnitude of memory B cell responses. Concurrent with their analyses of the IgG response, the authors noted an increase in IgE production in their mouse model. Indeed, TFR deletion resulted in greater quantities of autoreactive antibodies of both IgG and IgE isotypes, some of which overlapped in antigen specificity. This led the authors to characterize the presence and role of TFH and TFR within a house dust mite (HDM) sensitivity model. They observed that TFH within the HDM model produced low levels of IL-13 and that TFR were capable of suppressing TFH proliferation and IL-13 production in vitro. Thus, when TFR were deleted during HDM sensitization, plasma cells produced more IgE, although the B cell compartment was not broadly affected otherwise. The consequence of this increased IgE production is a greater infiltration of eosinophils and granulocytes within the lung and the development of more severe lung pathology. Thus, this series of experiments imply that absence of TFR cells during germinal center formation results in dysregulated humoral immunity and tissue damage upon repeated antigen exposure.

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