Tetraspanin-5–mediated MHC class I clustering is required for optimal CD8 T cell activation

Abstract

MHC molecules are not randomly distributed on the plasma membrane but instead are present in discrete nanoclusters. The mechanisms that control formation of MHC I nanoclusters and the importance of such structures are incompletely understood. Here, we report a molecular association between tetraspanin-5 (Tspan5) and MHC I molecules that started in the endoplasmic reticulum and was maintained on the plasma membrane. This association was observed both in mouse dendritic cells and in human cancer cell lines. Loss of Tspan5 reduced the size of MHC I clusters without affecting MHC I peptide loading, delivery of complexes to the plasma membrane, or overall surface MHC I levels. Functionally, CD8 T cell responses to antigen presented by Tspan5-deficient dendritic cells were impaired but were restored by antibody-induced reclustering of MHC I molecules. In contrast, Tspan5 did not associate with two other plasma membrane proteins, Flotillin1 and CD55, with or the endoplasmic reticulum proteins Tapasin and TAP. Thus, our findings identify a mechanism underlying the clustering of MHC I molecules that is important for optimal T cell responses.

Glycosylation differentially affects immune cell-specific tetraspanins CD37 and CD53

“…This hypothesis would imply that the total pool of tetraspanin proteins in a cell is separated in many different functional groups based on the attached glycosylation groups. In line with this hypothesis, CD151 was shown to exclusively co-IP highly glycosylated CD82 [41], and MHC-I was found to interact exclusively with lowly glycosylated Tspan5 [42].…”

The versatile roles of testrapanins in cancer from intracellular signaling to cell–cell communication: cell membrane proteins without ligands

“…CD9, CD82 have been revealed to interact with MHC II complex in APCs, which might facilitate the formation of MHC II multimers and subsequent CD4 + T cell activation [ 122 ]. One latest study demonstrated that TSPAN5 could promote the formation of intense MHC I clusters for CD8 + T cell activation [ 24 ]. On the contrary, CD37, CD151, CD63 on APCs exhibit suppressors of MHC presentation [ 125 ].…”

“…Other partners of TSPANs include growth factor receptors (EGFR [9], mtTGF-β [10]), transporters (ASCT2 [11], FATP1 [12], MDR1 [13]), membrane-linked kinases (BTRC [14], SOCSS3 [15], ATXN3 [16]), other transmembrane proteins (ADAM10 [17], CD44 [18], p120 [19]). Thus, TSPANs can affect several signaling pathways, including PI3K/AKT, Wnt/β-catenin, ERK1/2, STAT3/5, Src, Notch pathways communication, drug resistance and cancer immunology [16,[23][24][25][26] (Table 2). Specifically, TSPANs have been shown to regulate the biogenesis, cell-specific attachment of exosomes [19], and TSPAN4 can even promote the formation of migrasomes [27].…”

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

“…11 Indeed, following their engagement, the corresponding TCRs themselves can form nanoclusters, so potentially calibrating the extent of pMHC clustering -a metric of intracellular antigen dosage that could influence the way T cells respond. 12,13 How the results of Ochoa et al 1 might relate to the microcluster speculation is the main subject of the present review. It begins with the hypothesis of Burnet 14 that antigen concentration might distinguish between normal immune and tolerogenic responses, thereby ensuring the destruction of potential anti-self-immune cells.…”

“…11 Indeed, demonstrations of peptide-specific clustering of pMHCs are deemed consistent with intracellular pMHC enrichment before surface display. 13 5 | SPECIFIC pMHC MICROCLUSTERS Amid a sea of MHC proteins bearing a variety of peptides corresponding precisely to self, there are pMHC microclusters on 'membrane rafts' at the surface of presenting cells. 9,10,12 Here cognate peptides correspond to 'near-self' or, less frequently, to 'non-self'.…”