How Does Gluten Activate T Cells?

When we eat protein, enzymes in our digestive system (called proteases) break apart the chain into individual amino acids. In our intestine, cells called enterocytes absorb the amino acids so they can be used to fuel our bodies and rebuild our own proteins.

When humans eat gluten, it is not completely digested into individual amino acids in the small intestine. Gliadin, specifically, is difficult for our bodies to digest because it contains a high proportion of two amino acids—proline and glutamine. Because it is only partially digested, small fragments of the gliadin protein chain remain as peptides. This happens in people with and without celiac disease.

Antigen presenting cells located in the intestine take up the undigested gliadin peptides and display them on their surface with an MHC class II molecule. CD4+ T cells with receptors shaped like “locks” that match gliadin peptide “keys” mistakenly recognize gluten as a harmful pathogen and become activated. This begins the immune response.

Once CD4+ T cells become activated, they can produce different subsets of helper T cells (as described here). In celiac disease, the most common type of helper T cell produced is Th1, which produces cytokines, such as interferon gamma, that recruit other immune cells and cause tissue damage. There is also evidence for Th17 cells in celiac disease. Th17 cells produce interleukin-17, which is a key cytokine involved in several different autoimmune diseases.¹

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1. Jabri B, Sollid LM. T Cells in Celiac Disease. J Immunol. 2017;198(8):3005-3014.

Amino acids – Small units that are linked together by bonds to form proteins.

Antigen presenting cell – A specialized immune cell that presents peptides to CD4+ or CD8+ T cells. Peptides are presented by MHC I or MHC II proteins.

Cytokines – Small proteins that are made and released by immune cells. Allows cells to send signals and provide instructions to other cells.

Enterocytes – Cells that make up the intestinal lining. Responsible for absorbing nutrients.

Gliadin – One of the wheat proteins that forms gluten. Responsible for triggering an immune response in patients with celiac disease.

Gluten – A type of protein found in cereal grains. Wheat gluten is made of two proteins called gliadin and glutenin.

Helper T cell – Adaptive CD4+ immune cell that produces cytokines when activated.

MHC class II protein – Major histocompatibility complex class II protein. Found on the surface of antigen presenting cells. Presents peptides to CD4+ T cells.

Peptide – A small protein fragment consisting of a chain of amino acids.

Protease – A type of enzyme that breaks up proteins into smaller parts.

Receptor – A protein that is located on the surface of a cell and interacts with other proteins. Receptors act as the “locks” that recognize specific pathogen “keys”.

T cell – A type of adaptive immune cell. Also called T lymphocyte.