T cell stemness and ST6Gal-I mediated sialylation

Abstract

Populations of both CD4 and CD8 T cells with stem-like properties have been documented in the setting of autoimmunity, chronic infection, and cancer. These cells exhibit the capacity to self renew, as well as serve as progenitors to more differentiated T cell phenotypes, but the cell intrinsic factors that promote the development and maintenance of T cell stemness are not well known. In a mouse model of chronic intestinal inflammation, we observed that a subset of effector CD4 T cells displayed many of the attributes consistent with T cell stemness; these cells expressed the key stemness transcription factor TCF1, could persist long term in vivo, and further transitioned into terminal effector cells. Importantly, these stem-like effector CD4 T cells were able to both sustain and confer intestinal inflammation. To discern molecules that contribute to the stemness phenotype, we employed gene set enrichment analyses with multiple data sets and identified the glycosyltransferase ST6Gal-I, which facilitates the addition of a2,6-linked sialic acid moieties to surface N-glycans. We found that this sialyltransferase was preferentially expressed in stem-like CD4 T cells during colitis and CD8 T cells during chronic lymphocytic choriomeningitis virus infection, and that these cell populations displayed a2,6-linked sialic acids on the cell surface. Moreover, in the colitis model, we observed that genetic deletion of ST6Gal-I in T cells correlated with diminished TCF1 expression and reduced inflammation. Furthermore, constitutive expression of ST6Gal-I by T cells was associated with the ability to promote intestinal inflammation. Together, these data highlight ST6Gal-I as a potential regulator of the T cell stemness phenotype.

N-linked glycans: an underappreciated key determinant of T cell development, activation, and function

“…In agreement with this observation, ST6Gal-I −/− mice were more prone to autoimmune disease due to increased abundance and enhanced responsiveness of T H 1 and T H 17 CD4 + T cells [120] . Later evidence linked high levels of ST6Gal-I expression and activity to the expression of the transcription factor TCF-1 by a pathogenic population of CD4 + T cells that chronically produced IFN-γ and in turn, promoted intestinal inflammation [121][122][123] . Taken together, these findings highlight the pivotal role of α2,6 sialylation of N-linked glycan in regulating the differentiation of CD4 + T cells.…”