CD9 Regulates Major Histocompatibility Complex Class II Trafficking in Monocyte-Derived Dendritic Cells

Abstract

Antigen presentation by dendritic cells (DCs) stimulates naive CD4 ϩ T cells, triggering T cell activation and the adaptive arm of the immune response. Newly synthesized major histocompatibility complex class II (MHC-II) molecules accumulate at MHC-II-enriched endosomal compartments and are transported to the plasma membrane of DCs after binding to antigenic peptides to enable antigen presentation. In DCs, MHC-II molecules are included in tetraspanin-enriched microdomains (TEMs). However, the role of tetraspanin CD9 in these processes remains largely undefined. Here, we show that CD9 regulates the T cell-stimulatory capacity of granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent bone marrow-derived DCs (BMDCs), without affecting antigen presentation by fms-like tyrosine kinase 3 ligand (Flt3L)-dependent BMDCs. CD9 knockout (KO) GM-CSF-dependent BMDCs, which resemble monocyte-derived DCs (MoDCs), induce lower levels of T cell activation than wild-type DCs, and this effect is related to a reduction in MHC-II surface expression in CD9-deficient MoDCs. Importantly, MHC-II targeting to the plasma membrane is largely impaired in immature CD9 KO MoDCs, in which MHC-II remains arrested in acidic intracellular compartments enriched in LAMP-1 (lysosome-associated membrane protein 1), and MHC-II internalization is also blocked. Moreover, CD9 participates in MHC-II trafficking in mature MoDCs, regulating its endocytosis and recycling. Our results demonstrate that the tetraspanin CD9 specifically regulates antigenic presentation in MoDCs through the regulation of MHC-II intracellular trafficking.

C-type lectin-like receptor 2 (CLEC-2)-dependent DC migration is controlled by tetraspanin CD37

“…This is in accordance with studies showing impaired migration of Cd37-/-DCs in vivo (Gartlan et al, 2013;Jones et al, 2016). In DC biology, tetraspanin interactions with adhesion receptors or MHC molecules are particularly important for antigen presentation and T cell activation (Sheng et al, 2009;Gartlan et al, 2010;Jones et al, 2016;Rocha-Perugini et al, 2017). Now, we demonstrate a specific role for CD37 in controlling CLEC-2 function in migration of DCs.…”

Lamin A/C augments Th1 differentiation and response against vaccinia virus and Leishmania major

“…BMDCs were generated as described in ref. 39 . BMDCs were obtained from bone marrow cell suspensions after culture on non-treated cell culture dishes in complete RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 mg/ml penicillin, 100 mg/ml streptomycin, 50 mM 2-ME, and 20 ng/ml GM-CSF (PeproTech, London, UK).…”

Properties and functions of adipose tissue macrophages in obesity

“…The authors note a lack of differential expression of CD11c in these populations, so future studies will need to clarify the functional role of CD9 in ATMs as well as other AT stromal cells. CD9 high adipocyte progenitors 41 have been identified as correlating with AT fibrosis in humans, and CD9 is also found on DCs 42 to control antigen presentation, suggesting a potential broader role for CD9 in AT biology that has yet to be understood.…”