Mitf Regulates Gene Expression Networks Implicated in B Cell Homeostasis, Germinal Center Responses, and Tolerance

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Mar 6

PMID 38444862

Authors

Abhimanyu Amarnani

Maria Lopez-Ocasio

Ramile Dilshat

Kamala Anumukonda

Jonathan Davila

Nikita Malakhov

Chongmin Huan

Erna Magnusdottir

Eirikur Steingrimsson

Christopher A Roman

Affiliations

Soon will be listed here.

Abstract

Introduction: The Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure.

Methods: Two complementary mouse models of Mitf and MiT deficiency were used: the Mitf systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways.

Results: Both models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Fas background. In both models, RNAseq of resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation.

Discussion: These studies clarify Mitf's role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity.

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