Adaptive Immunity

T Cells

Major Histocompatibility Complexes

The major histocompatibility complex is a series of proteins found on all cells except red blood cells; it is also known as the human leukocyte antigen system.

T cells can recognize their target antigen only if that antigen is bound to a major histocompatibility complex (MHC) protein, a set of proteins that presents antigens on the surface of cells to support recognition by antigen receptors. MHC molecules signal to the immune system whether a cell is healthy or has been infected through presentation of pathogenic antigens on the cell surface. All cells in the body except for red blood cells express MHC proteins on their cell surface. There are two types of MHC molecule. Major histocompatibility complex I (MHC I) is a set of proteins found on all nucleated cell types that are derived from intracellular proteins and present antigens on the cell's surface, which are recognized by CD8+ T cells. This can include antigens derived from a pathogen or self-antigens, antigens derived from normal cell proteins that indicate that a cell is healthy. Major histocompatibility complex II (MHC II) is only found on antigen-presenting cells, such as dendritic cells, macrophages, and B cells, and is used by these cells to present antigens picked up from extracellular sources, such as other dying cells or proteins secreted from other cells, which are recognized by CD4+ T cells.

MHC I and MHC II present different antigens because the proteins that the antigens are derived from differ. Since MHCI and MHCII present different antigens, each activates a different subset of T cells. MHC I molecules preferentially activate CD8+ cytotoxic T cells, which engage in direct killing of infected cells, while MHC II molecules activate CD4+ helper T cells, which secrete cytokines.

Both MHC I and MHC II molecules can exist in several different forms, which differ in the amino acids in a specific part of the MHC protein responsible for antigen binding. Every person has a unique composition of subtypes of MHC I and MHC II molecules in their body. The amino acid differences between these subtypes mean that each differs slightly in the specific antigens it is able to bind. In each cell, proteins are processed by the proteasome, which breaks a full protein into many peptides, protein strands of up to 20 amino acids in length. Some of these peptides can be presented by MHC molecules. All MHC molecules can bind antigens derived from any protein, but the individual short peptide sequences that result from protein degradation will bind with differential strength to different MHC subtypes. Furthermore, MHC I can present short peptides of up to 10 amino acids long while MHC II is able to present longer peptides of 13–25 amino acids. These differences in MHC between individuals can cause susceptibility to or protection from different infectious diseases, autoimmune diseases (diseases that result when the immune system attacks healthy organs in the body), and cancer.

Classes of MHCs

Major histocompatibility complex proteins present antigens to activate T cells.

Structure and Maturation of T Cells

T cells are generated in the bone marrow, develop their specific receptors in the thymus, and are activated by antigen-presenting cells, such as B cells and macrophages.

T cells mediate cell-mediated immunity, an immune reaction that utilizes the ability of T cells to kill other cells without the involvement of antibodies, proteins that can be secreted from or bound to the surface of B cells and recognize antigens. T cells begin their life cycle in the bone marrow, where, like B cells, they are derived from hematopoietic stem cells. T cell specificity is determined in the thymus, an immune organ that is specialized for the production of T cells.

In the thymus, T cells undergo both positive and negative selection. First, positive selection identifies T cells that are capable of binding to MHC molecules. T cells must be able to engage with MHC-expressing cells in the thymus and receive a positive signal that allows their survival through the complete differentiation process. T cells that are unable to bind to MHC molecules die as a result of not receiving a signal during positive selection.

Once only T cells that can bind to MHC molecules remain, the next step in the life cycle of a T cell is negative selection. This process removes T cells that react too strongly with self-antigens, antigens that are present on normal, healthy cells in the body. These cells, if released into circulation, could cause autoimmune diseases. Negative selection protects people from a high likelihood of developing these diseases; however, negative selection is not perfect, and some autoreactive T cells, or T cells able to recognize and attack normal healthy tissue, can sometimes enter circulation as well.

Around 98% of T cells die in the thymus by failing either positive selection or negative selection. The remaining 2% comprise an individual's T cell repertoire, the collection of antigens an individual’s T cells recognize. This includes T cells specific to a variety of potential antigens that a person may encounter throughout their life, such as the flu and the common cold.

These T cells then leave the thymus and begin to move to sites throughout the body. Most T cells will enter into a lymph node, one of many small immune organs located throughout the body that are sites of adaptive immune cell activation. In lymph nodes, T cells encounter antigen-presenting cells such as B cells and dendritic cells and macrophages, MHC II-expressing cells of the innate immune system that activate T cells that recognize a particular antigen, leading to T cell proliferation. Interleukin-2 is an important protein secreted by activated T cells that supports T cell survival during this proliferation and for the rest of the life of a T cell.

T cells are most commonly activated when they encounter an antigen-presenting cell and the antigen receptor on the T cell binds to an antigen-bound MHC molecule on the antigen-presenting cell. However, there is another way to activate T cells, and that is using a superantigen, a molecule that can broadly activate T cells independent of antigen recognition. Superantigens instead activate T cells nonspecifically by linking the MHC II molecule on an antigen-presenting cell with T cell receptors by binding the side of the MHC II and T cell's receptor molecules. This activation is very strong and overwhelms the immune system, which can support the progression of disease and cause more problems for a patient. Bacteria such as Staphylococcus and Streptococcus and viruses including the Epstein-Barr virus (EBV) can make superantigens during an infection, and artificial superantigens are also a useful tool in the laboratory to study T cell activation.

Types of T Cells

The types of T cells include effector, helper, memory, regulatory, mucosal-associated invariant, gamma delta, and beta selection.

There are many different kinds of T cells that serve different purposes in the immune system. T cells are needed to kill infected cells, protect against autoimmunity, and suppress inflammatory responses at different times during an immune response. These T cells work with each other and with other kinds of immune cells during the course of an immune response.

There are three very prevalent kinds of T cells in the body: effector T cells, helper T cells, and regulatory T cells. Every T cell expresses either CD4 or CD8 on its cell surface. CD4 and CD8 are molecules that can be used to identify different populations of T cells, and these molecules functionally help to stabilize the interaction between MHC molecules and the T cell receptor. Effector T cells are the most common type of T cells and are activated by antigen-presenting cells to recognize and kill infected cells. Effector T cells express CD8 on their cell surface, and this molecule can be used to identify these cells. Effector T cells are also known as killer T cells. A killer T cell is a T cell capable of destroying other cells. Cytotoxicity refers to the ability of a T cell to kill other cells. Effector T cells know which cells to kill by recognizing a foreign antigen presented on MHC I with their specific T cell receptor. Helper T cells recognize MHC II on antigen-presenting cells, and this causes helper T cells to secrete a type of protein called a cytokine, which supports other immune cells involved in the immune response by driving immune cell activity and inflammation. Regulatory T cells, conversely, secrete proteins that suppress an immune response and induce immune tolerance, a state of unresponsiveness to something that should elicit an immune response. Both helper and regulatory T cells express a molecule known as CD4 on their cell surface. Regulatory and helper T cells can be distinguished from each other by the presence of immune-stimulating or immunosuppressive molecules.

Cell-Mediated Immunity

Several types of T cells function together to mediate an immune response to foreign cells. When a helper T cell is triggered by an antigen-presenting cell, it secretes cytokines that recruit other cells. Memory T cells that recognize the antigen differentiate into killer T cells and reproduce rapidly. The killer T cells bind to the foreign cells and kill them by releasing cytotoxic granules and through other means.
There are other types of T cells that are less prevalent throughout the body but serve important functions in specific organs. Mucosal-associated invariant T cells (MAIT) are one such subtype. Unlike conventional T cells, MAIT have a limited number of different antigen receptors that they are able to express. These cells are common in the intestines and help protect against bacterial and fungal infections in the gut. Another type of T cell that has a limited range of antigen receptors that they can express are called gamma delta T cells. These T cells can be found at mucosal sites such as the gut and the respiratory tract, as well as in the skin.

Finally, there are T cells in the thymus that have not yet undergone selection. These T cells are unique in that they may not express a functional T cell receptor that is able to recognize antigens. The production of an antigen receptor by a T cell requires rearrangement of genes. Sometimes this rearrangement process goes awry, and the genes are arranged in such a way that no functional receptor is made by the cell. These cells only exist in the thymus and are killed during positive selection because of their inability to bind to MHC molecules.

Major Subclasses of T cells

T cell type Surface receptor, MHC recognized Function
Effector (also, killer or cytotoxic) CD8, MHCI Destroy infected cells
Helper CD4, MHCII Signal natural killer and macrophages with cytokines
Regulatory CD4, MHCII Immunosuppression
Mucosal-associated invariant T (MAIT) CD8 and others, MHCI-like Cytokine secretion and infected cell destruction
Gamma delta Other, MHC-independent Multifunctional, signalling, cell destruction, antigen-presentation

Different types of T cells promote, restrain, and carry out immune responses.