Destabilization of peptide:MHC interaction induces IL-2 resistant anergy in diabetogenic T cells

Abstract

Autoreactive T cells are responsible for inducing several autoimmune diseases, including type 1 diabetes. We have developed a strategy to induce unresponsiveness in these cells by destabilizing the peptide:MHC ligand recognized by the T cell receptor. By introducing amino acid substitutions into the immunogenic peptide at residues that bind to the MHC, the half life of the peptide:MHC complex is severely reduced, thereby resulting in abortive T cell activation and anergy. By treating a monoclonal diabetogenic T cell population with an MHC variant peptide, the cells are rendered unresponsive to the wild type ligand, as measured by both proliferation and IL-2 production. Stimulation of T cells with MHC variant peptides results in minimal Erk1/2 phosphorylation or cell division. Variant peptide stimulation effectively initiates a signaling program dominated by sustained tyrosine phosphatase activity, including elevated SHP-1 activity. These negative signaling events result in an anergic phenotype in which the T cells are not competent to signal through the IL-2 receptor, as evidenced by a lack of phospho-Stat5 upregulation and proliferation, despite high expression of the IL-2 receptor. This unique negative signaling profile provides a novel means to shut down the anti-self response.

The tryptophan metabolite picolinic acid suppresses proliferation and metabolic activity of CD4+ T cells and inhibits c-Myc activation

“…However, the PA-induced state of hyporesponsiveness could not be overcome by the addition of exogenous IL-2, which has been demonstrated to break "classic" T cell anergy [42]. In this respect, recent works have indicated that states of IL-2 resistant anergy might exist in T cells [43]. It remains to be explored further whether a specific molecular signature is induced by pretreatment with PA and whether anergy-associated genes, such as Cbl-b [44][45][46], are involved in this hyporesponsive state.…”

Mechanisms of autoimmunity in the non‐obese diabetic mouse: effector/regulatory cell equilibrium during peak inflammation

“…At the first level, additional T-cell subsets are progressively recruited to the inflammatory reaction. For example, low-affinity [56][57][58] and anergic [59][60][61] T cells are reactivated in situ by repeated and sustained antigen-specific sensitization and local inflammation. At the second level, cytokines and vacant niches for lymphocyte expansion exert differential effects on spontaneous and homeostatic expansion of T cells with variable affinities to selected epitopes.…”

Suboptimal stimulation by weak agonist epitope variants does not drive dysfunction of HIV-1-specific cytotoxic T lymphocyte clones

“…T cell anergy is a state of antigen-induced hyporesponsiveness that is involved in diseases such as cancer and autoimmune diabetes [9,10]. It is a non-deletional mechanism of peripheral T cell tolerance thought to have evolved to prevent reactivity to self-antigens [11], and has the hallmarks of defective proliferation and IL-2 production [12,13].…”

“…An initial conceptual model was first characterized using murine CD4 + T cell clones given antigenic stimulation in the absence of both IL-2 and CD80/CD86 co-stimulation [14]. More recently it has been demonstrated that T cell anergy can also be induced via suboptimal antigen stimulation by "altered peptide ligands" (APL) with reduced/suboptimal affinity for the TCR, resulting in incomplete signaling and activation [10,[15][16][17][18]. While most demonstrations have utilized CD4 + T cells, there is evidence for this phenomenon in CD8 + T cells as well [19][20][21][22].…”