T cell mediated immunity pt 1

antigen-presenting cells (APCs)

present antigens to T cells

• major APCs: macrophages, dendritic cells and B cells

T cell dependent antigens

T cells only identify PEPTIDES

MHC antigen combination

T cell recognize MHC and processed antigen (peptide) seperately with seperate receptors

MHC class I

cytotoxic T cells (CD8): produce toxic agents to kill targets

MHC class II

• helper T cells (CD4): stimulate B cells to make antibodies, stimulate T cells to become active

• regulatory T cells (CD4): suppress immune responses

why two MHC complexes?

• the two MHC activate the two branches of the adaptive immune system

  • MHC 1 combats intracellular pathogens

  • MHC 2 combats extracellular pathogens

• the two MHCs enhance one branch of immunity (cytotoxicity vs antibodies) depending on the infection

adaptive immune response

1. APCs (dendritic cells) encounter pathogen at site of infection

   • dendritic cells are main cell type capable of activating adaptive immune system

2. APCs engulf pathogen

3. APCs migrate lymphatic vessels

4. APCs migrate to a regional draining lymph node

5. at lymph node, APCs encounter naive T cells

antigen processing and presentation by dendritic cells

• receptor-mediated endocytosis: MHC class II (CD4 T cell)

• macropinocytosis: MHC class II (CD4 T cell)

• viral infection: MHC class I (CD8 T cell)

• cross-presentation: MHC class I (CD8 T cell)

chemokine signals

• CCR7 surface receptors bind to CCL21 chemokines

• chemokine signals direct dendritic cells into lymph node AND they can no longer process more antigens

mature dendritic cells encounter naive T cells

• HEV: high endothelial venules

• when specific T cell receptor binds to MHC with peptide, T cell is selected and retained in lymph node

• native T cell is activated to differentiate and proliferate into effector T cells

activation of CD4 (helper) T cell

• CD4 (helper T) cells are the most prevalent type of T cells in blood and lymphatic organs

  1. interaction of MHC: antigen complex with T cell receptors

  2. interaction of CD28 receptor with B7-1/B7-2 protein of APC

importance of co-stimulator

• co-stimulator B7 is exclusively expressed by APCs

  • not exclusively expressed: depends on presence of infection

• toll-like receptors on/in dendritic cell generate signals to induce B7 expression

T-cell anergy

state that T cells reach in the absence of B7 co-stimulation

• T cells without second signal will not respond to external signal, reach an inactivated state: fail to make IL-2

naive/activated T cells express different forms of IL-2 receptor

• naive: low affinity, γβ

• activated: high affinity, γβα

IL-2 role

leads to differentiation and proliferation of T cells

1. naive T cell express low affinity IL-2 receptor

2. interaction of MHC:TCR induce expression of IL-2 in T cells

3. co-receptor signal enhances expression

4. activated T cell express a third component of receptor

5. high affinity IL-2 receptor assembled

6. IL-2 binds to high affinity receptor inducing proliferation of T cell

7. leads to population of T cells with same antigenic specificity (clonal population)

functional types of effector CD4 (helper) T cells

• Treg cell: FOXP3; regulation, suppression of inflammatory responses

• TH17 cell: inflammation

• TH2 cell: allergic and helminth responses

• TFH cell: germinal centre help

• TH1 cell: macrophage activation, inflammation

what determines effector class of CD4 (helper) T cells

• type of cytokines in immediate environment

• types of cytokines they secrete

• function in adaptive immunity

effector CD4 (helper) T cells

never directly attack pathogen but help other cells mount a successful immune response

TH1

• IL-12 and IFN-γ differentiate CD4 cells to TH1 cells

• stimulate macrophages

• secrete IL-2: promote differentiation and proliferation of cytotoxic T cells

  • high TH1 = cytotoxic immune response

• promotes delayed hypersensitivity

TH2

• IL-4 differentiate CD4 cells to TH2 cells (produced by basophils)

• promotes defense against larger, multicellular parasites

• production of IgE by B cells

• humoral immune response (need lots of antibodies)

TH17

• IL-6 and TGF-β

• secrete IL-17 (induced by IL-23)

  • leads to production of CXCL8 which recruits neutrophils

  • stimulates nearby host cells to produce pro-inflammatory cytokines (attract macrophages)

• high IL-17 = inflammation immune response

  • beginning of immnune response

TFH (follicular helper T cells)

• induced by IL-6

• stimulate B cells to make antibodies in secondary lymphoid organs/tissues

• involved in class-switching and somatic hypermutation

• humoral immune response

Treg

• control or regulate immune response

• prevent immune response from targeting normal microbiota

  • no regulation = severe inflammation, auto-immune disorders

• express TCR and CD25

• express high levels of transcription factor FoxP3 (master regulator)

Treg mechanisms

1. inhibitory cytokines

2. cytolysis

3. metabolic disruption

4. targeting dendritic cells

inhibitory cytokines

• reduce effect of other T cells

• expression of immunosuppressive cytokines

• TGF-β, IL-10, and IL-35

cytolysis

• secretion of granzymes and perforin to promote apoptosis

• leads to reduction of cytotoxic and other T cells

metabolic disruption

• overexpression of CD25 which acts as a receptor to IL-2

• scavenging IL-2 lowers immune response intensity

• surrounding effector T cells die due to cytokine deprivation

• CD39 and CD73 produce adenosine: act as immune suppressor

targeting dendritic cells

• CTLA-4 has high affinity to CD80/CD86 (B7) and outcompetes co-stimulatory signals via CD28

• leads to producing of IDO (immunosuppressive molecule)

• LAG3 binds to MHC-II and inhibits maturation

memory T cells

• DO NOT require CD28 mediated co-stimulatory signal to be activated

• can be activated by signals from T cell receptor upon binding appropriate peptide-MHC complex

• influenced by cytokine signals

• upon encounter to specific antigen, will differentiate and proliferate into effector T cells

kinetics of T cell response

• activated naive T cells begin to proliferate and differentiate reaching peak of effector cells between 7 and 10 days

  • short-lived cells, die as infection is cleared

• long-lived memory T cells remain and can be reactivated years later with same pathogen