Immunology Adaptive Immunity T Cells

T lymphocytes basics

- constitute the cellular arm of adaptive immunity

- central role in...

+ controlling the acquired immune response

+ crucial effector cells (cytotoxic activity and cytokine production)

+ essential for elimination of intracellular pathogens

types of T cells

- two major subsets

+ CD4 T cells

+ CD8 T cells

T cell receptor complex structure

- transmembrane heterodimer with variable and constant region

- monovalent (can only bind 1 antigen)

- number of TCR we could make estimated at 10^10

- also does somantic recomibination

the T cell receptor complex signaling

- the T cell receptor complex on its own is insufficient to transduce an activation signal to the T cell cause of short cytoplasmic tail

- needs CD3 and zeta chain dimer proteins to transmit signal into the cell (same in every T cell)

lymphatics overview

- part of immune system

- drain extracellular fluid from the peripheral tissue through LN into thoracic duct, empties into subclavian vein

lymph nodes

- small, bean shaped glands

- part of lymphatic system

- filter lymph fluid

- can be found isolated or in groups

- enlarge in response to injury, inflammation, or in development of tumor

- common sites for swollen nodes are neck, groin, and axilla

why does lymph matter for T cells?

- antigen presenting cells such as macrophages or dendritic cells present antigens via MHC complexes

- APCs travel to lymph nodes nearby

- T cells in the lymph node may become activated if they bind to the antigen

- T cells then migrate to site of infection to help eliminate microbes

accessory molecules in T cell activation

- multiple surface molecules participate in T cell activation

- adhesion molecules (CD4, CD8, CD2, LFA-1)

- co-stimulatory molecules (CD28, CD40)

- co-receptors (CD4, CD8)

CD28

- a co-stimulatory molecule on the T cell that binds to the APC (B7)

- this produces a second signal which is necessary for T cell activation

anergy

- T cell receptor binds to MHC on APC but there is no binding of CD28/B7

- leads to inactivation or deletion of T cell

cytotoxic T cells binding

- express CD8 but not CD4

- bind to MHC class I

- about 35% of peripheral blood T cells

helper T cells binding

- express CD4 but not CD8

- bind to MHC class II

- about 65% of peripheral blood T cells

CD4+ T cells or T helper cells function

- main function is to augment or potentiate immune responses by secretion of cytokines that activate other leukocytes to fight off infection

two types of CD4 T cells

- both from Th0 cell

- Th1: cell-mediated immunity, pro-inflammatory cytokines

-Th2: antibody-mediated immunity, anti-inflammatory cytokines

what determines if a Th0 cell becomes Th1 or Th2?

- not exactly known but some proposed options are:

1) nearby cytokine environment

2) nature of antigen

3) concentraction of antigen

4) nature of co-receptor signals involved

Th1 cytokines

-IFN-y, IFN-a, IL-2, IL-12, IL-23

Th2 cytokines

- IL-4, IL-5, IL-6, IL-10

Th17 cells

- produces IL-17

- IL-23 induces IL-17 production in Th17 cells

- located in skin and lining of GI tract

IL-17

- extremely potent pro-inflammatory cytokine

- recruits neutrophils to site of infection

Th17 diseases

- some diseases have been found to have high Th17 involvement:

1) Crohn's disease (inflammation of small intestine)

2) ulcerative colitis (inflammation of large intestine)

3) psoriasis

CD8+ T cells

- majority are cytolytic cells

- major function is to kill

- bind MHC class I (intracellular antigens)

cytolytic T cell lysis steps

1) recognize appropriate antigen and become activated

2) contents of membrane bound cytoplasmic granules discharged by exocytosis

3) perforin inserts itself into plasma membrane of target cell

4) granzymes, serine proteases, can then enter the cell and cleave precursors of caspases (creates caspases)

5) caspases are molecular scissors

6) lead to target cell destruction by apoptosis (cytolytic cell survives)

T cell selection

- T cells need to be able to recognize antigen in the context of MHC, therefore, they must be able to recognize MHC

- cells that do not recognize MHC die

- cells that are strongly activated by self MHC plus self peptides are eliminated in thymus (die by apoptosis)

- goldilocks (needs to be just right)

nude mice

- mice engineered to not have T cells for some reason don't have hair

DiGeorge syndrome

- rare congenital disease

- absent (

SCID

- severe combined immune deficiency

- abscence of T and B cells (or non-functioning)

- also known as bubble boy disease

- can be treated with gene therapy or bone marrow transplant

tolerance

- inability to make an immune response to an antigen

clonal deletion

- loss of self-reactive lymphocytes in thymus and bone marrow

clonal anergy

- occurs in periphery if co-stimulatory signal is absent (CD28)

immunological ignorance

- interaction does not lead to activation

- low level of low affinity self-reactive T cells

regulatory T cells

- lymphocutes that suppress immune responses, can be antibody or cell-mediated

- have autoimmune-inhibitory activity

5-10% of CD4+ cells, express TCR alpha-beta

Treg cell characteristics

- recognize peptide in conjunction with MHC class II

- express CD25 (IL-2a chain)

- express transcription factor Foxp3

- IL-2 is vital

- activated Treg secrete large amounts of IL-10 and TGFb (inhibitory cytokines)

- TCRs of Tregs tend to recognize self-peptides; require less peptide to get activated

without Treg...

- in mice leads to spontaneous occurence of some autoimmune diseases

- nude mice develop autoimmune disease if given Treg depleted CD4 T cells

- problems with Foxp3 in both humans and mice leads to devastating autoimmune disorders

- low number is related to pregnancy complications