• T cells are lymphocytes that directly or indirectly eradicate pathogens.
• They respond to intracellular targets, as opposed to the B cells of the humoral arm, which respond to extracellular microbes.
• Key events in the life cycle of the T cell:
  — They arise from stem cells in the bone marrow.
  — T cells mature in the thymus (T is for Thymus): maturation involves positive and negative selection, and gives rise to naïve (non-activated) cells defined by the presence of either CD4 or CD8 proteins on their surfaces.
  — In the secondary lymphoid organs, such as the lymph nodes and spleen, naïve T cells are activated by antigens; the naïve T cells become functional effector cells.
  — After the pathogen is eradicated, most of the effector cells undergo apoptosis; otherwise, they pose a potential danger to the host cells.
  — Some of the T cells differentiate to become memory cells, which will respond if/when the host is exposed to the same antigen – thus, the secondary response to subsequent exposure can occur much faster.

MHC

Major Histocompatibility Complex (MHC) molecules present peptide antigens that activate T-cells.

Class I MHC molecules

• Present fragments of antigens that are synthesized endogenously – i.e., peptides derived from viral antigens produced within the cells.
• Class I MHC molecules are only recognized by naïve CD8+ T cells and their Cytotoxic T cell descendants.

Class II MHC molecules

• Present fragments from extracellular microbes and pathogens – i.e., peptides derived from extracellular microbes.
• Class II MHC molecules are only recognized by naïve CD4+ T cells and their Helper T cell descendants.

T CELL MATURATION

• In the histological sample, we indicate the cortex of a lobule, which is where positive selection occurs, and, the medulla, which is where negative selection occurs.
• “Thymic education” entails two selective mechanisms that eliminate T cells that would otherwise harm the host:
  — In positive selection, immature T cells are exposed to cortical epithelial cells displaying self-MHC complexes:
  The T cells that recognize the MHC complexes survive
  Those that fail to recognize the MHC complexes undergo apoptosis.
  — Then, in negative selection, T cells are exposed to MHC complexes with self-antigen:
  Those T cells that do NOT respond to the self-antigen survive
  The T cells that DO respond undergo apoptosis.
  — Thus, positive selection ensures that the surviving T cells can recognize the MHC complex, which is necessary for their activation, while negative selection ensures that self-destructive T cells are eliminated.
  — Ultimately, thymic maturation produces three main types of T cells, which we designate based on their unique cell surface proteins: CD8+, CD4+, and CD4+/CD25+.
  CD4+/CD25+ T cells are Regulatory T cells; they can suppress the activity of the other T cell types via expression of Cytotoxic T Lymphocyte Antigen 4 (CTLA-4).
  — In addition to the CD proteins, naïve T cells also express receptors (T-Cell Receptors, TCRs) for specific antigens; binding with their specific antigen induces their activation.

T CELL ACTIVATION

• Activating Cells:
  — MHC class I molecules are displayed by all nucleated cells (in other words, most body cells except red blood cells).
  — MHC class II molecules are displayed by dendritic cells, macrophages, and B cells – because of this unique ability, these are referred to as “antigen-presenting cells.”
  However, be aware that B cells do not activate naïve T cells; they stimulate mature Helper T cells as part of their own activation (discussed in detail, elsewhere).
  — As we learned earlier, CD8+ and CD4+ T cells recognize different MHC classes; this means that they can only be activated by cells displaying the appropriate MHC molecules.
• A general example:

1. An antigen-presenting cell, such as a dendritic cell, recognizes and engulfs a microbe.
2. It digests the microbe and re-packages a peptide fragment with an MHC class II molecule on its surface.
3. The MHC- antigen complex is recognized by a naïve CD4+ cell, which is subsequently activated. Notice that if the antigen-presenting cell displayed only antigens complexed with MHC class II molecules, the CD4+ cell would not have recognized it.

Activating mechanisms in more detail:

• 2-signal activation of a CD8+ T cell, which differentiates to become a cytotoxic cell.
  — The cell surface of the CD8+ has the T-cell Receptor Complex (TCR complex), which consists of the following components:
  The T-cell receptor, which is specific to the peptide antigen displayed by the MHC molecule; CD3 proteins; and, the CD8 protein, which recognizes and interacts with the MHC class I molecule of the nucleated cell.
  — The representative nucleated cell displays the class I MHC – antigen complex.
  — The interaction between the TCR complex and nucleated cell allows for the second signal, which involves co-stimulationbetween CD28 and B7-2.
  — Activation triggers proliferation, aka, cloning, of the T cell and differentiation into the effector type – which, for CD8+ cells, is the Cytotoxic T cell.
  These processes are guided by cytokines, which are released by T cells and antigen-presenting cells.
• 2-signal activation of a CD4+ T cell, which differentiates to become a Helper T cell.
  — The dendritic cell surface displays the MHC II-antigen complex.
  — The CD4+ cell has the TCR complex: the T-cell receptor, which is specific to the antigen; the CD3 molecules; and, the CD4 protein that interacts with the MHC II molecule on the antigen-presenting cell.
  — The second signal comprises co-stimulation: interaction between CD28 on the surface of the T cell and B7-2 on the dendritic cell.
  — Activation results in proliferation and differentiation to effector cells.

Effector Cell Functions:

• Cytotoxic T cells directly kill pathogen-bearing cells via the following steps:

1. The T cell recognizes the MHC I – antigen complex.
2. Docking brings the two cell membranes in close association.
3. The T cell releases perforins, which form a pore in the infected cell’s membrane.
4. The cytotoxic cell releases granzymes, which move through the pore and trigger apoptosis of the infected cell.

• Helper T cells, the products of activated CD4+ cells, have multiple roles in both innate and adaptive responses:
  — They amplify the innate response via cytokine release and recruitment of neutrophils and macrophages.
  — They activate B cells, which mediate the humoral arm of the adaptive immune response.
  — They activate cytotoxic T cells, in part by upregulating the expression of co-stimulatory molecules on dendritic cells.
  — Superantigens, such as Staphylococcus bacteria, are super potent activators of CD4+ cells.

• 4 subsets of Helper T cells:
  — Under the influence of interferon-gamma and IL-12, cells of subset Th1 develop.
  They engage in anti-viral activity, macrophage activation, and induce cytotoxic T cell differentiation; when unregulated, they are associated with autoimmune diseases.
  This subset produces IL-2 and interferon-gamma.
  — Under the influence of IL-4, Th-2 develop.
  This subset is particularly important in defense against worms and in mobilization of eosinophils; they are associated with allergies and asthma.
  They produce IL-4, IL-5, and Il-13.
  — Tissue growth factor-beta, IL-6, IL-1, and IL-23 induce differentiation of subset Th17, which recruit neutrophils and monocytes.
  They are also associated with autoimmune disease.
  They produce IL-17 and IL-22.
  — Follicular helper T cells differentiation is thought to require interaction with B cells.
  Follicular helper T cells promote the humoral immune response and produce IL-21.