The roles of Nr4a1 in T cell development and activation

Rouvray, Sophie (2023). The roles of Nr4a1 in T cell development and activation. University of Birmingham. M.Sc.

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Abstract

Nr4a receptors are activated upon T cell receptor (TCR) signalling and are thought to play redundant roles in T cell development and activation. Of the three Nr4a members, Nr4a1 expression is highly sensitive to TCR signals and is expressed during positive and negative selection in the thymus. The Nr4a1 receptor is also emerging as a therapeutic target within autoimmunity and cancer due to its negative regulatory functions. Understanding the function of Nr4a1, therefore, is of both fundamental and therapeutic interest. We utilised Nr4a3-Tocky mice as a tool for following NFAT-driven TCR signalling. Nr4a3-Tocky mice were crossed onto an Nr4a1-/- or Nr4a1+/- background. We compared T cell expression of Nr4a3-Timer and CD25 between Nr4a3-Tocky Nr4a1+/- to the Nr4a3-Tocky Nr4a1-/- mice. To determine the functional role of Nr4a1, ELISA’s were used to measure interleukin-2 (IL-2) and interferon-γ (IFN-γ) produced by naïve CD4+ T cells activated in vitro and RNA-seq performed to analyse transcriptomic changes. We saw Increased evidence of TCR signalling in ex vivo analysis of Nr4a1-/- thymic T cells at all stages of development when compared to Nr4a1+/-. In contrast, no significant difference was observed within peripheral T cells from the spleen. We observed a significant increase in CD4SP CD25+ Treg cells within the Nr4a1-/- mouse, and Treg were enriched for apoptotic cells. Functional analysis revealed a redundant role for Nr4a1 in the control of IL-2 expression in activated CD4+ T cells. Our findings indicate that the absence of Nr4a1 results in more self-antigen driven signalling within the thymus and an expansion of autoreactive CD25+ Treg and Treg precursors. Nr4a1 appeared functionally redundant during peripheral T cell activation. We conclude that Nr4a1 may induce short-lived and T cell developmental stage-dependent effects that warrants further investigation.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):