T Cells in Celiac Disease

Abstract

Celiac disease is a human T cell-mediated autoimmune-like disorder caused by exposure to dietary gluten in genetically predisposed individuals. This review will discuss how CD4 T cell responses directed against an exogenous Ag can cause an autoreactive B cell response and participate in the licensing of intraepithelial lymphocytes to kill intestinal epithelial cells. Furthermore, this review will examine the mechanisms by which intraepithelial cytotoxic T cells mediate tissue destruction in celiac disease.

Fig.1. Integration of celiac disease-associated genes involved in celiac disease pathogenesis by affecting T-cell regulation, T-cell responses and T-B cell interactions

Shown in red are non-HLA candidate genes identified by genome wide association studies and known to be involved in thymic T cell differentiation (Themis and Runx3), T cell activation (SH2B3, TAGAP, PTPN2, CD28, CTLA4, CIITA, IL2/IL21), differentiation of inflammatory CD4 T cells (IRAK1, IL12A, IL18RAP/IL18R1, IL1RL1/IL1RL2, STAT4), B cell activation and differentiation (ICOS/ICOSLG, CD28, IL21/IL2, RGS-1, IRF4, RGS1, BACH2, ARHGAP31, POU2AF1), and effector cytolytic T cell migration and functions (IL21/IL2, RGS1, MAP3K7, CCR1,2,3, CCR4, UBASH3). Names of candidate genes are indicated according to their potential involvement in immunological pathways. Sites depicted include sites of T cell differentiation (thymus), T and B cell priming (lymph nodes), and the intestinal mucosa.

Fig 2. Posttranslational modification and T-cell recognition of deamidated gluten peptides in celiac disease

In a) schematic representation is given whereas in b) interactions based on a crystal structure (PDB: 4OZH) are depicted. Transglutaminase 2 (TG2) mediates deamidation of gluten peptides by targeting glutamine residues (Q) preferentially in the sequence QXP (X is any amino acids, P is proline) and converting them to glutamate (E). Shown is a sequence that gives rise to the DQ2.5-glia-α2 epitope. This epitope docks in the peptide-binding site of the HLA-DQ2.5 molecule with the generated glutamate residue (p-E4, in red) buried in the P4 pocket. On recognition of peptide-MHC complex, the TCR of a T-cell clone (S16) (69) makes contact with three peptide residues (in green; glutamine (Q) at position 2, a leucine (L) at position 5 and a tyrosine (Y) at position 7). An arginine residue of the TCR CDR3β loop (R109, blue) is particularly involved in the interaction making contact both to DQ2.5 residues and the p-L5 residue. As can be seen in the lower panel, this TCR residue does not interact directly with the p-4E residue of the peptide.

Fig 3. Tissue resident intestinal intraepithelial cytotoxic CD8 T lymphocytes mediate killing of epithelial cells based on recognition of stress signals

In lymph nodes naïve CD8 T cells require to receive co-stimulatory signals via CD28 to become activated and differentiate into cytotoxic effector T cells. In tissues, effector CTLs that have down-regulated CD28, require receiving a distinct set of activating signals to unleash their effector functions. These activating signals are provided by activating natural killer receptors NKG2D and CD94/NKG2C, which recognize MICA/B and HLA-E induced on epithelial cells by stress and inflammation in active CD. Under these conditions activating natural killer receptors enable IE-CTLs that are not gluten-specific, to kill intestinal epithelial cells directly or indirectly by lowering the T cell receptor threshold and allowing recognition of low affinity epithelial or microbial antigens.