T-cell development, activation, regulation, and effector function

Specificity

Innate immune cells can only recognize pathogens bearing surface molecules that are common to many pathogens and conserved over evolution

T cell receptor (TCR) structure

• Transmembrane heterodimers composed of either an α and a β chain or a γ and a δ chain (αβ T cells and γδ T cells)

• Extracellular “variable” regions contain the antigen binding region

The two classes of TCR’s

TCR complex

• A functional TCR is in a complex with 4 transmembrane polypeptides collectively called CD3 (γ, δ, ε, and ζ chains) – these help transduce signals to activate the T cell

• CD3 is not a receptor, does not bind ligand but is essential for intracellular signaling

• CD4 or CD8 will also associate with the TCR (except γδ T cells)

TCR complex- MHC interaction

• CD4 binds to MHC Class II on antigen-presenting cell

• CD8 binds to MHC Class I on antigen-presenting cell

T cell diversity

• Occurs within the corticomedullary junction of thymus → cortex

• The germline arrangement of the TCR gene contains multiple segments

• These segments are semi-randomly rearranged (Combinational diversity)

• Additional diversity occurs when random nucleotides are added or deleted at the joining of segments (junctional diversity

• This arrangement is independent of antigen

Combinational diversity

• β-chain genes are rearranged by random joining of segments (D, J)
   The new DJ segment is linked with a V segment = new VDJ segment

• α-chain genes are rearranged by random joining of segments (V, J)
   = new VJ segment

Junctional diversity

During this process, random nucleotides are removed or added between the segments

T cell specificity (Positive selection)

• Occurs in cortex of the thymus

• DP (double positive) thymocytes interact with cortical thymic epithlelial cells that express both MHC I and MHC II

• Cells that can interact with MHC-peptide complexes are given survival signals and live

• Cells that do not interact die by apoptosis (up to 96%)

• Those that bind well to MHC I lose CD4 expression and become CD8+ T cells

• Those that bind well to MHC II lose CD8 expression and become CD4+ T cells

T cell tolerance (Negative selection)

• Occurs in medulla of thymus

• Medullary Thymic epithelial cells are able to express many proteins usually found in other tissues in the body

• Antigen presenting cells in the medulla present peptides from these many proteins

• If the thymocyte binds too well it will be negatively selected and die

• Destruction of self-reactive thymocytes is called central tolerance

T regulatory cells (Treg)

• Immunosuppressive T cells that can help prevent autoimmune responses in the periphery

• This is a type of “peripheral tolerance”

• A mechanism that takes place outside primary lymphoid organs that prevent immune responses against self or harmless materials like food or commensals

γ δ T cells

• A small fraction of T cells in most mammals (In ruminants and chickens these cells are the majority)

• Do not express CD4 or CD8

• Do not require MHC: antigen interaction but can recognize unprocessed antigen (without MHC)

• Often are mucosally associated

• Less diverse repertoire because of few V gene segments

• Cytotoxic function (similar to CD8+ T cells)

The 3 signals necessary for T cell activation

1. Antigen

2. Co-stimulation

3. Cytokines

T cell activation: signal 1

• Naive T-helper (CD4) and T-cytotoxic (CD8) cells that have exited the thymus can migrate to lymph nodes

• They can be activated only by antigen presenting cells (almost always a dendritic cell) presenting a specific antigen

T cell activation: signal 2

• CD80/86 molecules on the antigen presenting cell must interact with CD28 molecules on the T cell

• CD80/86 is only expressed on antigen presenting cells and in low levels unless the APCs are activated by cytokines, pathogens or T cells (“danger signals”)

• Other co-stimulatory molecules can also play a role in activating T cells

T cell activation: signal 3

• Cytokines in the environment or produced by the APC will provide this signal and help determine the fate of the T cell by providing context

• Determines the phenotype of the T cell

• T cells will begin to secrete IL-2

• When bound to IL-2, the high affinity IL-2 receptor induces T cell proliferation

T helper (CD4) cell

• Recognizes MHC class II

• Seen on antigen-presenting cells

• Directs and boosts other immune cells

• Release cytokines to give signals that tell other cells what to do

T-cytotoxic (CD8) cell

• Recognizes MHC class I

• Found on almost all nucleated cells

• Kill infected, cancerous or foreign cells

• If a cell displays a foreign or abnormal peptide (from a virus or a mutated protein) they destroy it

Naive T cells

Inexperienced, circulates through lymph nodes, needs full activation, slow first response, not bound to antigen

Effector T cells

Active fighter, short-lived, makes cytokines or kills, found at infection sites, bound by antigen

Memory T cells

• These T cells for a specific antigen may persist for years or a lifetime

• Provide long-lasting protection against previously encountered microorganisms