What is MHC and why does it matter?

The major histocompatibility complex (MHC) genes code for proteins which the immune system uses to identify cells and tissues in the body as “self” or “other”.  MHC molecules ‘talk’ to T cells which patrol the body for foreign invaders or dangerously mutated cells. The MHC acts as a window into our cells. It presents snippets of information (peptides) on the state of the cell- allowing the immune system to check for infection, cancer, and other maladies. Cells that do not pass the self/other test are eliminated.

The MHC genes are polymorphic, and individual organisms from the same species very rarely have the same MHC identity. When looking for a donor for organ or tissue transplantation, both the donor and recipient MHC identities are determined, to find the best and closest match. Your MHC identity is also called your “tissue type”. This tissue type is critical in organ transplantation- mismatches make grafted or transplanted tissues a target for the adaptive immune system.

MHC molecules are comprised of two individual parts that present short epitopes (short peptides) to cells of the immune system.  There are two main classes of MHC molecule – Class I and Class II. There are also “non-canonical” MHC types which serve specialized purposes and present specialized molecules.


Class I MHC molecules are found on all nucleated cells in the body and on platelets. Class I interacts with CD8+ T cells, interacting directly with CD8 as a co-receptor. Presentation of intracellular epitopes allows T cells to check for intracellular bacteria, viral infection and cancerous mutations. MHC I presentation and signaling is a global “alarm” system for the cells in the body.

The Class I MHC molecule is made of 2 proteins- a three-domain alpha unit non-covalently bonded to beta-2 microglobulin. The amino acid sequence and shape of these subunits determines the shape of the binding groove and therefore what peptide can bind.  MHC Class I present epitopes of 8-10 amino acids to T cells, typically derived from proteins in the cytosol (endogenous protein antigens).

Class II MHC molecules are typically found on antigen presenting cells (APC) such as macrophages, dendritic cells, and B lymphocytes. These MHC molecules interact with CD4 on CD4+ T helper cells.  Class II MHC presentation functions as a specific line of communication between immune cells and the global immune system.

The Class II molecule is made up of two distinctive subunits- alpha and beta, which are non-covalently linked to form the binding groove. In that groove, epitopes derived from extracellular contents are presented in 14-18 amino acids peptides. Class II MHC presentation is a requirement for initiating and sustaining adaptive immune responses against foreign invaders such as fungi and extracellular bacteria.

This same family of proteins in humans are called Human Leukocyte Antigens (HLA).


Featured Image via pixabay : https://pixabay.com/en/blood-cells-red-medical-medicine-1813410/


  1. Thank you. This was very helpful to me; I only recently began studying immunology and I have so much to learn! Your diagram of MHC I and MHC II allowed me to translate the genetics to a molecule I could “see.”


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