Abstract
A subset of T regulatory cells (Tregs), identified by TIRC7 (T cell immune response cDNA 7) expression is designated as Immune Regulatory 1 Cells (IR1 cells). TIRC7 is an immune checkpoint inhibitor, co-localized with the T- cell receptor, HLA-DR and CTLA-4 during T-cell activation, which delivers regulatory signals via binding to its ligand, HLA-DR α2 domain. IR1 cells express FOXP3, and multiple other markers associated with immune suppression. They constitute as much as 10% of Tregs. IR1 cells strongly inhibit proliferation in mixed lymphocyte reactions, where they express high levels of IL-10. Ex vivo expansion of Tregs over 2 weeks in the presence of an agonist TIRC7 antibody disproportionately expands the IR1 Treg subset, while maintaining high expression of suppressive markers including CD39, IL-10, LAP and GARP. Ex vivo expanded IR1 cells are a potent, homogeneous, stable set of suppressor Tregs with the potential to modulate immune dysregulation. The characteristics of IR1 cells suggest a therapeutic advantage over polyclonal Tregs for therapeutic interventions. Early restoration of immune homeostasis using IR1 cells has the potential to fundamentally alter the natural history of conditions characterized by abnormalities in the T regulatory cell compartment.
Highlights
Thymus-derived T lymphocytes form the basis of cellular immunity in humans
We have previously identified TIRC7 (T-cell immune response cDNA 7) [7, 8], a multimembrane spanning protein, co-localized with the T cell receptor, HLA-DR and CTLA-4 [9, 10], which is induced within hours of T cell activation [11]
IR1 Cells Are Found in the CD25hi/med Compartment of T regulatory cells (Tregs)
Summary
Thymus-derived T lymphocytes form the basis of cellular immunity in humans. T cells perform a wide range of functions, including the initiation and maintenance of immune response and memory. It is important to identify functional subgroups to optimize therapeutic Treg cell interventions [5, 6] To this end, we have investigated the association of key measures of T-regulatory cell suppressive activity, and the presence of the immune surface marker TIRC7, in human T-regulatory cells. During solid organ transplant rejection, TIRC7 expression is increased in the allograft and decreased in peripheral blood lymphocytes [18]. This dynamic is consistent with highly specialized expression in areas of ongoing inflammation and immune activation. We have developed agonist antibodies to TIRC7 to expand IR1 cells ex vivo, an essential step towards exploring clinical applications
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