A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8⁺ T cells

Abstract

Several previous studies outlined the importance of the histone H2A deubiquitinase MYSM1 in the regulation of stem cell quiescence and haematopoiesis. In this study we investigated the role of MYSM1 in T-cell development. Using mouse models that allow conditional Mysm1 ablation at late stages of thymic development, we found that MYSM1 is intricately involved in the maintenance, activation and survival of CD8 T cells. Mysm1 ablation resulted in a twofold reduction in CD8 T-cell numbers, and also led to a hyperactivated CD8 T-cell state accompanied by impaired proliferation and increased pro-inflammatory cytokine production after ex vivo stimulation. These phenotypes coincided with an increased apoptosis and preferential up-regulation of p53 tumour suppressor protein in CD8 T cells. Lastly, we examined a model of experimental cerebral malaria, in which pathology is critically dependent on CD8 T cells. In the mice conditionally deleted for Mysm1 in the T-cell compartment, CD8 T-cell numbers remained reduced following infection, both in the periphery and in the brain, and the mice displayed improved survival after parasite challenge. Collectively, our data identify MYSM1 as a novel factor for CD8 T cells in the immune system, increasing our understanding of the role of histone H2A deubiquitinases in cytotoxic T-cell biology.

Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review

“…It is important to note however that these experiments were limited to a small set of putative MYSM1-regulated loci [41,45], and thus do not rule out existence of other mechanistic links between Mysm1-deficiency and p53 activation. The studies were also conducted primarily in lymphoid precursor cells [41,45], while a conditional deletion of Mysm1 in these cells in vivo has minimal impact on lymphocyte development [49,50], stressing the importance of conducting further mechanistic studies on the cross-talk between MYSM1 and p53 in earlier hematopoietic precursors and HSCs.…”

“…To characterize the checkpoints in lymphocyte development and adaptive immune response regulated by MYSM1, independently of MYSM1 functions at the earlier stages of hematopoiesis, we performed a deletion of Mysm1 at different stages of B and T cell development in Cre/loxP mouse models [49,50]. Surprisingly, Mysm1-deletion from the pro-B cell stage (mb1-Cre) resulted in a mild depletion of B cell numbers, while Mysm1-deletion at the pre-B cell stage (CD19-cre) or in mature follicular B cells (CD21-cre) allowed the normal numbers of B cells to be maintained [50].…”

“…To characterize MYSM1 functions within the T cell lineage, independently of its roles at earlier stages of hematopoiesis, we performed a conditional deletion of Mysm1 in Cre/loxP mouse models [49].…”

“…Deletion of Mysm1 in the thymus from the double-negative 3 (DN3, Lck-Cre) or the double-positive (DP, CD4-Cre) stage in T cell lineage development resulted in normal thymocyte numbers and normal progression of thymic T cell development [49]. In peripheral lymphoid organs, mild depletion of CD8 T cells and elevated expression of activation markers on both CD8 and CD4 T cells were observed [49].…”

“…Deletion of Mysm1 in the thymus from the double-negative 3 (DN3, Lck-Cre) or the double-positive (DP, CD4-Cre) stage in T cell lineage development resulted in normal thymocyte numbers and normal progression of thymic T cell development [49]. In peripheral lymphoid organs, mild depletion of CD8 T cells and elevated expression of activation markers on both CD8 and CD4 T cells were observed [49]. T cell responses to in vitro stimulation were also altered, with CD8 T cells showing elevated cytokine production, reduced induction of granzyme B, impaired proliferation, and increased apoptosis, while CD4 T cells showed only impaired proliferation [49].…”