T-cells in infection Flashcards
Why do we need more than antibodies?
Antibodies are capable of identifying viral surface proteins, bacterial wall components, and other extracellular pathogenic material. But it is incapable of recognizing a cell that has been infected with a virus. Once the virus has been ingested into cells, the viral particles are often processed naturally by the metabolic functions of the cell, and fragments of these displayed on thecells surface via MHC receptors. however, antibodies are not capable of identifying these processed antigenic fragments. Therefore, other immune effectors are required to deal with already infected cells.
Humoral vs cell-mediated immunity
Humoral immunity
This denotes immune factors working extracellularly. Antibodies, the product of B cells, are used to identify, neutralize, and opsonise extracellular pathogenic entities such as bacteria and viruses. They are only effective against antigens that are outside of cells.
Cell mediated immunity
This occurs as a product of T cells. When activated, T cells do not form antibodies but rather they can use their T-cell receptors to identify virus-infected cells. They do this because their TCR can identify intracellular antigens that are displayed on cell surfaces. This is vital for viral infected cells, abnormal protein products form damaged cells such as tumurous cells, or transplanted organs.
Cytotoxic T cells
Cytotoxic T cells are a type of T cells that are known for actively killing other infected cells. They have a T-cell receptor devised of an alpha and beta chain, which recognizes MHC I receptors (which are present on all nucleated cells). They use the co-factor molecules CD8 to assist in binding to antigens on MHCI receptors, and have CD3 as a transmembrane protein to relay internal cell signalling.
Once activated, they release perforins and granzymes to kill infected cells.
Helper T cells
Helper T cells, similar to cytotoxic T cells, have a T cell receptor consisting of an alpha and beta chain. They have a co-receptor as well but this one is CD4, and it helps the T cell bind to MHC class II receptors (which are only found on professional antigen presenting cells).
Once activated by an antigen (in this case antigen X), this activated T helper cell will release cytokines and hormones which act in an autocrine or paracrine fashion to activate and modulate the activity of surrounding immune cells. They will also aid in the activation of B and T cells by binding to the MHC II receptors of these cells, which have also been activated by the same antigen (X), and cause activation of these cells.
Class I and II HLA
HLA are the genes that encode the MHC receptors on human cells. Multiple genes contribute to the creation of MHC I and MHC II molecules.
Class I
Class I HLA denote 3 genes, HLA-A,B, and C, which are polymorphic and codominant, meaning both the HLA-A genes recieved from your mother and father are used to create MHC molecules. The unique combination of these genes is used to create MHC surface proteins.
Class I MHC are expressed on all nucleated cells, and present peptides to cytotoxic T cells (CD8+ cells)
Class II
Similarly, the 3 genes, HLA-DP,DQ, and DR are also polymorphic and codominant, and its the combination of these molecules that create the specific MHC II molecules.
Class II MHC are expressed only on professional antigen presenting cells, such as dendrites, macrophages, and B cells. They present peptides to CD4+ T helper cells.
How MHC I gets foreign peptides
When a virus is endocytosed by a cell, they will hijack the cellular machinery in order to produce more viral proteins, the replication of these viral proteins and enzymes will allow a new virus to be assembled within the cell and released from the cell to infect more cells.
However, in normal cellular matabolism proteins will be broken down and processed, combined with MHC I molecules and presented on the cellular surface for the immune system.
T cell antigen recognition
The T cell will then come into contact with this virally infected cell. its CD8 co-receptor recognizes a non-polymorphic conserved region on the MHC molecules, and the TCR recnogizes the antigen. Together, this helps activate the T cell.
T cell clonal activation
When a dendrite or free bacteria enter the lymph nodes, they encounter hundreds of inactive T cells. All of these T cells have a single TCR specificity on their surface. If the dendrocyte or bacteria within the lymph nodes contains the antigen to these specific TCR, then this will partially activate the T cell. In order to confirm that this is not a self-antigen, helper signals from T helper cells are required for full activation. The T helper cell will secrete soluble factors like cytokines and hormones, as well as directly bind (following its own activation by the same antigen).
Following this, the T cells will prolfierate and differentiate. They will form either memory cells, which are long lived cells that recirculate and do not require as many helper signals to be activated.
Or they form cytotoxic T cells which leave the lymph nodes in search of pathogens to kill.
Antigens and class II MHC
Unlike the MHC I molecules, MHC II is only present on APC cells. The cell will selectively uptake pathogenic material, that has specific antigens. Following this phagocytosis, this antigenic material will be processed and combined with MHC II, which is then presented on the surface of the cell.
T cell clonal activation (helper cells)
Very similar to the previous activation of cytotoxic T cells.
An APC that has processed antigenic material puts this in an MHC II molecule and presents it to the T helper cell baring the same antigen specificity. The CD4+ cell will use its co-receptor to identify the non-polymorphic highly conserved region of the MHC II molecule, and the TCR recognizes the antigen. This, in addition with helper signals (presumed to be from other acctivated helper cells?) causes the helper cells to prolfierate and differentiate. They eithe form memory cells (Longer life, recirculate, less fussy about help) or become cytokine secreting activated helper cells that modulate other cells responsiveness and activity.
Lymphocyte activation follows a 2 step process
1st step:
Surface receptor binding of high enough affinity to stimulate receptors like surface immunoglobulins on B cells or T cell receptors.
However, this signal on its own is not enough for full activation, although it does create the capacity of the cell to respond to step 2.
2nd step:
Helper cells that produce 2 types of signals
- Soluble signals such as cytokines and hormones
- surface interactions by co-stimulates.
