T lymphocytes do not recognize antigens directly

T lymphocytes do not recognize antigens directly, but do so after the antigen is processed and presented on the surface of an antigen-presenting cell associated with a cell surface glycoprotein, which is coded for by the MHC. This glycoprotein is termed the MHC class II molecule. Histocompatibility molecules are classified into two major groups: class I molecules (which regulate interactions between CD8+ cells and target cells), and class II molecules (which regulate inter-actions between CD4+ cells and antigen-presenting cells).

The function of both class I and II MHC molecules is to present antigen to T cells, thus initiating the adaptive immune response. T cells are able to interact with the histocompatibility molecules only if they are genetically identical; this phenomenon is known as MHC restriction.

      1. In humans, the MHC is located on chromosome 6. It is divided into four major regions: A, B, C, and D. The A, B, and C regions code for class I molecules, and the D region codes for class II molecules. The histocompatibility leukocyte antigen (HLA) complex comprises more than 200 genes. The class I genes code for the a-polypeptide chain of the class I molecule, whereas the beta2-microglobulin gene, on chromosome 15, encodes for the b-chain of the class I molecule, and is the light chain of the class I molecule. The a-chain has four domains: two peptide-binding domains (a1 and a2); one immunoglobulin-like domain (a3), and the last domain is the cytoplasmic tail. The class II molecules contain a and b polypeptide chains, which are encoded by the class II genes. The class II genes are also found on chromosome 6 and have a special system used for designation and nomenclature of their loci. Specifically, three letters are used. The three letters signify class, family, and chain. The first letter is always a D and indicates the class. The second letter is an M, O, P, Q, or R and represents the family. The third letter in the series is an A or B and represents the a or b chain, respectively. In addition, each of the class II a and II b chains has four domains: the peptide-binding domain (a1 or b1), the immunoglobulin-like domain (a2 or b2), the transmembrane region, and the cytoplasmic tail.

With rare exception, class I genes are expressed on all cells of the body, whereas class II genes are primarily expressed by antigen-presenting cells, such as B cells, dendritic cells, macrophages, some activated T cells, and thymic epithelial cells. Class I and II molecules process antigen differently. Class I molecules process intracellular proteins that are marked by ubiquitin. The proteins unfold and enter proteosomes, where they are processed and degraded into peptides. Next, they enter the endoplasmic reticulum. The peptide is then transported to the outer surface of the cell and bound to the HLA I molecule. Class II molecules degrade extracellular proteins via a different pathway. These are taken into the cell via invaginations, which pinch off and form endocytic vesicles. These vesicles join with lysosomes and at this point, the peptides are exposed to proteolytic enzymes. The lysosome–endocytic vesicle complex becomes known as an endosome. Once digested, the peptides are placed on the outer surface of the cell and are bound to the HLA class II molecules. MHC class II molecules lacking the peptide ligands are unstable and disassemble at low pH. MHC class II molecules require a ligand to occupy the peptide-binding groove in order to remain stable. Therefore, a peptide can be regarded as the “third subunit” of a mature MHC class II molecule. HLA-DM has been shown to bind the empty class II dimers and thus stabilize the groove in the absence of peptides.

T-cell receptors discriminate between MHC class I and II molecules. In general, CD8 cells bind HLA class I and down-regulate the expression of CD4 molecules, whereas CD4 cells bind class II and down-regulate the expression of CD8 molecules. Generally, CD4+ T lymphocytes become helper T cells and CD8+ T lymphocytes become cytotoxic T cells. As thymocytes enter the thymic cortex, they attempt to match their receptors with HLA peptide complexes on the cortical epithelial cells. If the receptors and ligands do not match up, which happens in the majority of cases, the thymocytes die via apoptosis mechanisms. A minority of thymocytes undergoes positive selection, in which these cells engage HLA peptide complexes and bind with low affinity. This low-affinity binding is sufficient to block apoptosis. Next, at the corticomedullary junction, the thymocytes are given the opportunity to undergo negative selection. At this point, they encounter antigen-presenting cells that express costimulatory molecules and proteases (cathepsins). This expression allows for a high-affinity interaction between the T-cell receptor and the HLA peptide. This interaction creates a signal instructing the thymocyte to undergo apoptosis. This process is termed negative selection and takes place so that self-reacting (or autoreactive) T cells, which can cause autoimmune disease, can be destroyed. Of all the progenitor cells that enter the thymus and proliferate in it, fewer than 1% mature into T cells. The MHC gene products have important roles in clinical immunology. For example, transplanted tissues are rejected if transplants are performed across MHC barriers.

     2. The majority of cellular immunity is mediated by the CD4+ cell, which is responsible for the following immune phenomena:

1.Delayed hypersensitivity reactions (e.g., tuberculin skin test response).
2. Contact sensitivity (e.g., poison ivy dermatitis).
3. Immunity to intracellular organisms.
4. Immunity to viral and fungal antigens.
5. Tissue graft rejection.
6. Elimination of tumor cells bearing foreign antigens.
7. Formation of chronic granulomas.