Engagement of SLAMF3 enhances CD4 ⁺ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus

Abstract

Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4+ T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naïve CD4 + T cells. Ligation of SLAMF3 receptors on SLE CD4 + T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2.

Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin‐2

“…Differences in STAT5 phosphorylation between SLE and controls is not a result of a diminished IL-2R expression on SLE CD4+ T cells. As we have previously shown, CD25 and CD122 expression is similar in SLE and controls [15]. In summary, these data emphasize that the phosphorylation of STAT5 upon IL-2 stimulation is defective in CD4+ T cells isolated from SLE patients.…”

“…In this context, our results suggest that strategy aiming at restoring IL-2 sensitivity of the CD4+ T cells, for example through increasing the expression of the IL-2R on CD4+T cell surface [15], should be considered in conjunction with low dose IL-2 treatment, because CD4+ T cells not only display decreased IL-2 production but also a defective response to IL-2.…”

Signaling Lymphocytic Activation Molecule Family Member 7 Engagement Restores Defective Effector CD8+ T Cell Function in Systemic Lupus Erythematosus

“…Decreased SLAMF7 expression in CD81 T cells from SLE patients. Expression of SLAMF7 was examined in T cells isolated from SLE patients (n 5 [16][17][18][19][20][21][22][23][24][25][26][27] and healthy controls (n 5 13-22). SLAMF7 was mostly expressed by CD81 T cells, as well as double-negative T cells, a T cell subset that expresses CD3 but has lost CD4 and CD8 expression (Figure 2A and Supplementary Figure 3A In contrast, expression of SLAMF7 on CD41 T cells was very low.…”

Viral CD229 (Ly9) homologs as new manipulators of host immunity

“…28 Although these studies point that CD229 functions as a negative regulator, other studies also suggest that CD229 may have an activating role in NK cells and CD4 + T cells that express the SAP adaptor. [29][30][31] the myeloid lineage. 32,33 As stated in the next section, infected cells can produce numerous viral molecules to inhibit both NK cell and CTL activation and effector functions, allowing viruses to escape from the immune system.…”

“…Moreover, Ly9 (CD229)‐deficient mice spontaneously develop features of systemic autoimmunity, such as the production of antibodies against dsDNA, nucleosome and antinuclear antibodies . Although these studies point that CD229 functions as a negative regulator, other studies also suggest that CD229 may have an activating role in NK cells and CD4 + T cells that express the SAP adaptor …”