T-cell activation

The adaptive immune response is highly specific for each invader. The cells of the adaptive immune response have receptors that differentiate one pathogen from another by their unique parts - called antigens. The key cells of the adaptive immune response are the lymphocytes - the B and T cells.

T cells develop in the thymus where they undergo a process called VDJ rearrangement to generate a massively diverse set of T cell receptors, or TCRs. There are two types of T cells which are identified based on molecules they express on their surface. Helper T cells express CD4 on their surface, and their main function is to support other immune cells. Cytotoxic T cells express CD8 on their surface, and their main function is to kill infected or cancerous cells. A T cell starts out naive and then gets primed or activated - at which point it differentiates into an effector or memory T cell and proliferates.

Activation of both helper and cytotoxic T cells requires two signals. The first signal occurs when a T cell receptor binds to an antigen; specifically, an antigen that’s a protein rather than carbohydrate or lipid. Now, protein antigens entering the body are first picked up by antigen-presenting cells like dendritic cells and taken to the lymphoid organs – which are home to the naive T-cells. The antigen-presenting cells then process the antigens and display them on molecules present on their cell surface called major histocompatibility complex, also known as MHC. MHC molecules act like serving platters to present the antigen to T cells. There are two types of MHC molecules that work with the two types of T cells. MHC class I molecules present antigen to CD8+ T cells and MHC class II molecules present antigen to CD4+ T cells. MHC class II molecules are found on the surface of an antigen presenting cell like a macrophage or dendritic cells while MHC class I molecules are found on all nucleated cells throughout the body.

The antigen presented on the MHC molecule must be the right size and shape to bind strongly to the T cell receptor, or TCR, which is closely associated with the CD3 protein complex on the T cell surface. The CD3 protein complex consists of 6 peptide chains, one gamma, one delta, two epsilon, and two zeta chains, forming three dimers; gamma-epsilon, delta-epsilon and zeta-zeta.

The TCR itself is composed of an alpha chain and a beta chain, each of which has two domains - a variable domain and a constant domain. The variable regions of the alpha and beta chains of the T cell receptor bind to the antigen presented by the MHC molecule. Whether it binds MHC I or MHC II depends on if the T cell expresses CD4 or CD8. The constant domain has a short transmembrane segment and a short cytoplasmic segment. The transmembrane segment contains cysteine residues which allow two adjacent chains to form a disulfide bond, connecting the chains to one another. And the variable domain of the alpha and beta chain come together to form a single antigen binding site. This is different from the B cell receptor which has two antigen binding sites. Also, unlike the B cell receptor, the T cell receptor is surface bound and cannot be secreted.

Now, in addition to the T cell receptor, CD4 binds to the MHC class II molecule and CD8 binds to the MHC class I molecule, and that helps secure the interaction between the T cell receptor and the MHC molecule. Second, the cytoplasmic portion of the alpha and beta chains of the T cell receptor are rather short. As a result, the signal that the T cell receptor has successfully bound an antigen, gets sent down other portions of the CD3 complex as well as the CD4 or CD8 molecules.

The second signal required for T cell activation is called co-stimulation. And it’s when a ligand that’s on the surface of a T cell called CD28, binds to a protein called B7 on the antigen presenting cell. Antigen presenting cells start expressing higher levels of B7 on their surface primarily when they encounter foreign antigens and also when there are inflammatory cytokines like interferon-gamma, IL-1 beta, and TNF-alpha around. Now, if a T cell sees its antigen without costimulation, it becomes anergic, meaning that the cell won’t get activated, even if it sees the antigen in the future. This extra layer of security prevents T cells from automatically getting turned on - just like how a cell phone needs to get “unlocked” to make a call - it prevents mistakes from happening. When a T cell and antigen presenting cell are interacting, the region where the T cell receptor is bound to MHC-antigen and either CD4 or CD8 and B7 is bound to CD28 is referred to as the immune synapse.