Malat1 is a determinant of CD4+ T cell function

In this thesis, we show that Malat1 is a critical regulator of one of the most fundamental transitions in the immune system, the differentiation of T helper (Th) cells from naïve CD4+ T cells. We determine that Malat1 down-regulation is a hallmark of Th cell differentiation, yet its deletion results in enhanced immunity in both in vitro and in mixed bone marrow chimera in vivo infection models. This is because Malat1-/- Th1 and Th2 cells produce lower levels of the anti-inflammatory cytokine IL-10. Mechanistically, we determine that Malat1 regulates the expression of IL-10 through the key transcription factor MAF. Notably, we show that Malat1 dependent regulation of IL-10 is female specific, as loss of Malat1 does not alter IL-10 expression in male CD4+ T cells in in vitro polarised Th2 cells or in an in vivo Schistosoma mansoni egg induced model of lung inflammation. Additionally, we find that Malat1 loss alters gene expression levels, which is reflected through impaired induction of the Th cell differentiation programme. . Next, through RAP-MS analysis, we determine the Malat1-RBP interactome in both EL4 cells (a T cell line) and primary naive CD4+ T cells. We determine that Malat1 interacts with multiple RBPs which include members of the hnRNP and SR protein families. Some of these interactions are unique to either EL4 cells or primary naïve CD4+ T cells with some core interaction partners identified in both cell types. Collectively, our results reveal that Malat1 is an essential orchestrator of CD4+ T cell function with relevance to immune health and pathology.