Soluble immunosuppressive checkpointome of mesenchymal stromal cells: Immunoregulatory mechanisms and a conceptual framework for potency assessment

Figure 2 The mesenchymal stromal cell soluble checkpointome and its cellular targets. Inflammatory licensing reconfigures the mesenchymal stromal cell (MSC) secretory programme. Established members (shaded) are proteins whose release by MSCs has been experimentally demonstrated and linked to a functional immunological outcome. Candidate members (unshaded) are checkpoint molecules of established immunological importance for which MSC-derived soluble forms have not yet been documented. Arrows denote engagement of the indicated receptor system and the downstream consequence. The net effect is tolerogenic conditioning of the local niche rather than the elimination of any single effector population. Each depicted outcome is bounded by the cited primary evidence: Galectin-1 knockdown restores T-cell proliferation but leaves non-alloreactive natural killer (NK) cells unaffected, so no NK or B-cell effect is attributed to galectin-1; galectin-9 is shown to suppress T and B cells as reported, and human leukocyte antigen-G5 to affect T and NK cells and regulatory T cells. Arrows denote reported functional associations, not proven direct molecular interactions. IFN-γ: Interferon gamma; TNF-α: Tumor necrosis factor alpha; IL: Interleukin; MSC: Mesenchymal stromal cell; PD-L1: Programmed death ligand 1; HLA-G5: Human leukocyte antigen-G5; HVEM: Herpesvirus entry mediator; BTLA: B- and T-lymphocyte attenuator; PD-1: Programmed death-1; TIM-3: T cell immunoglobulin and mucin domain-containing protein 3; ILT: Immunoglobulin-like transcript; NK: Natural killer.