Glycans as Key Checkpoints of T Cell Activity and Function

Abstract

The immune system is highly controlled and fine-tuned by glycosylation, through the addition of a diversity of carbohydrates structures (glycans) to virtually all immune cell receptors. Despite a relative backlog in understanding the importance of glycans in the immune system, due to its inherent complexity, remarkable findings have been highlighting the essential contributions of glycosylation in the regulation of both innate and adaptive immune responses with important implications in the pathogenesis of major diseases such as autoimmunity and cancer. Glycans are implicated in fundamental cellular and molecular processes that regulate both stimulatory and inhibitory immune pathways. Besides being actively involved in pathogen recognition through interaction with glycan-binding proteins (such as C-type lectins), glycans have been also shown to regulate key pathophysiological steps within T cell biology such as T cell development and thymocyte selection; T cell activity and signaling as well as T cell differentiation and proliferation. These effects of glycans in T cells functions highlight their importance as determinants of either self-tolerance or T cell hyper-responsiveness which ultimately might be implicated in the creation of tolerogenic pathways in cancer or loss of immunological tolerance in autoimmunity. This review discusses how specific glycans (with a focus on N-linked glycans) act as regulators of T cell biology and their implications in disease.

Keywords: N-glycosylation; T cells; autoimmunity; glycans; immune response; self-tolerance.

Figure 1

Glycans as a major connective chain that controls T cell response in either a tolerogenic or immunostimulatory scenario. Glycosylation appears to be central in regulating several steps of a T cell's life. During T cell development, different population of T cells (ETP, early thymocyte progenitor; DN1, 2, 3, and 4, double negative; DP, double positive; SP, single positive) display specific glycosylation patterns. The normal glycosylation of SP population results in an educated T cell function. However, by genetic, environmental or metabolic constrains, T cell glycosylation can be compromised re-directing immune system toward an immunostimulatory or tolerogenic response. Glycans are proposed here as key players in immune-unbalanced diseases, such as autoimmunity and cancer.

Figure 2

The hallmarks of glycans in T cell biology. N-glycans have a broad effect on the multiple T cell functions with impact both in autoreactivity and in immune tolerance. Particularly, the complex branched N-glycans catalyzed by beta 1,6-N-acetylglucosaminyltransferase V (GnT-V) (encoded by MGAT5 gene) have been demonstrated to control different T cells functions by targeting different T cells receptors (such as TCR, CD25, and CD4) and therefore regulating T cell proliferation, T cell differentiation, T cell signaling as well as the production of inflammatory cytokines. Alterations on GnT-V activity but also in alpha-mannosidase II (α-MII) as well as in N-acetylglucosaminyltransferase I (GnT-I, MGAT1 gene) and II (GnT-II, MGAT2 gene) activity were shown to compromise T cell homeostasis being associated with the development of several autoimmune disorders in humans and mouse models (such as EAE, IBD, SLE, TID). The FUT8-mediated core fucosylation of TCR was associated with hyperactivation of CD4⁺ T cells (T cells autoreactivity) whereas the modification of the co-inhibitory receptors (CTLA-4 and PD-1) by FUT8-mediated core fucose results in immune tolerance. The T cell development and T cell self-renewal are controlled by GnT-I-mediated glycosylation and by O-GlcNAcylation through OGT (O-GlcNAc transferase), respectively.