A recent study published in Frontiers in Immunology identified an expanded population of signaling lymphocytic activation molecule-associated protein (SAP)+ T peripheral helper (TPH) cells in both the circulation and kidney samples of patients with biopsy-confirmed lupus nephritis. The researchers suggested that this SAP+TPH cell population was functionally active and directly involved in the formation of in situ ectopic germinal centers. Additionally, they identified a GZMK+ SAP+ CD8 T cell population characterized by the expression of pro-inflammatory cytokine and chemokine genes.
Peripheral blood mononuclear cells (PBMCs) from 30 systemic lupus erythematosus (SLE) patients, including 10 with lupus nephritis (LN), were analyzed for SAP expression using spectral flow cytometry and single-cell RNA sequencing (scRNA-seq) data. The study found significantly higher levels of SAP-positive CD4 and CD8 T cells in SLE patients compared to controls. Notably, the TPH subset of CD4 T cells exhibited the highest SAP expression. This increase correlated strongly with disease activity, particularly in patients with LN. Additionally, scRNA-seq data revealed that SAP expression was localized in TFH-like CD4 T cells and GZMK+ effector CD8 T cells within the kidneys of LN patients.
The SLAM family comprises transmembrane co-receptors that play a crucial role in modulating antigen-driven T cell responses. Signal transduction downstream of the SLAM receptors is facilitated by SAP, a small intracellular adaptor protein characterized by a single SH2 binding domain. This domain enables SAP to recruit tyrosine kinases and protect phosphorylated sites from dephosphorylation. Properly balanced SLAM-SAP signaling within T cells is essential for maintaining healthy immune function, as both deficiency and overexpression of SAP can trigger autoimmune diseases. In lupus nephritis, SAP-expressing T cells contribute to the disease by promoting abnormal T-B cell interactions, leading to the production of autoantibodies and immune complex deposition in the kidneys. These immune complexes trigger an inflammatory response, causing kidney damage.
Recent research has highlighted the role of T follicular helper (TFH) and peripheral helper (TPH) cells in the pathogenesis of systemic lupus erythematosus (SLE). SAP is crucial in regulating these cells by interacting with signaling lymphocyte activation molecule family (SLAMF) receptors, which are vital for T cell-B cell interactions. These interactions drive B cell maturation into autoantibody-producing plasma cells, a hallmark of SLE. The expansion of SAP-expressing T helper cells is strongly associated with lupus nephritis in SLE patients.
Targeting the SLAM-SAP signaling pathway offers a promising therapeutic approach. By modulating SAP expression or disrupting its interaction with SLAMF receptors, it might be possible to reduce abnormal T-B cell interactions, decrease autoantibody production, and ultimately prevent or mitigate kidney damage in lupus nephritis.
References
- Gartshteyn Y, Geraldino-Pardilla L, Khalili L, Bukhari S, Lerrer S, Winchester RJ et l. SAP-expressing T peripheral helper cells identify systemic lupus erythematosus patients with lupus nephritis. Front Immunol. 2024 Mar 14;15:1327437.
- Gartshteyn Y, Askanase AD, Mor A. SLAM Associated Protein Signaling in T Cells: Tilting the Balance Toward Autoimmunity. Front Immunol. 2021 Apr 16;12:654839.