Abstract
Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell–cell interactions, fertility, cancer metastasis and immune responses. It has previously been shown that TSPAN32 knockout mice have normal hemopoiesis and B-cell responses, but hyperproliferative T cells. Here, we show that TSPAN32 is expressed at higher levels in the lymphoid lineage as compared to myeloid cells. In vitro activation of T helper cells via anti-CD3/CD28 is associated with a significant downregulation of TSPAN32. Interestingly, engagement of CD3 is sufficient to modulate TSPAN32 expression, and its effect is potentiated by costimulation with anti-CD28, but not anti-CTLA4, -ICOS nor -PD1. Accordingly, we measured the transcriptomic levels of TSPAN32 in polarized T cells under Th1 and Th2 conditions and TSPAN32 resulted significantly reduced as compared with unstimulated cells. On the other hand, in Treg cells, TSPAN32 underwent minor changes upon activation. The in vitro data were finally translated into the context of multiple sclerosis (MS). Encephalitogenic T cells from Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE) mice showed significantly lower levels of TSPAN32 and increased levels of CD9, CD53, CD82 and CD151. Similarly, in vitro-activated circulating CD4 T cells from MS patients showed lower levels of TSPAN32 as compared with cells from healthy donors. Overall, these data suggest an immunoregulatory role for TSPAN32 in T helper immune response and may represent a target of future immunoregulatory therapies for T cell-mediated autoimmune diseases.
Highlights
Tetraspanins are evolutionarily conserved cell-membrane proteins involved in a variety of biological functions, from cell adhesion to intercellular communication and signaling
Data are shown as normalized mean ± SD and statistical analysis performed using one-way ANOVA followed by Bonferroni multiple test correction
Since CD28 signaling is dependent on the PI3K/Akt/mTOR pathway, we investigated whether mTOR could promote a modulation in TSPAN32 levels
Summary
Tetraspanins are evolutionarily conserved cell-membrane proteins involved in a variety of biological functions, from cell adhesion to intercellular communication and signaling. No significant differences were observed in TSPAN32 levels after anti-CD3 stimulation and co-stimulation with anti-CTLA4, anti-ICOS or anti-PD1 antibodies (Figure 2B). In the Treg subset of CD4+ lymphocytes, a moderate decrease in TSPAN32 expression levels was observed upon activation, which reached statistical significance only at 5 h post stimulation (p < 0.05 vs the control unstimulated cells) (Figure 2D). Lower levels of TSPAN32 were observed in T effector cells as compared with Treg cells at 5 and 6 h post stimulation (p < 0.05). A decrease in TSPAN32 levels was observed for CD53 in T cells from MOG-immunized mice (p < 0.01) (Figure 5B). The analysis of the expression levels of pro-inflammatory cytokines in CD4 T cells from MOG-immunized mice showed significantly higher levels for TNFα (p < 0.05), IL-6 (p < 0.05) and IL-2 (p < 0.001) (Figure 5C).
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