T cell development and diversity

lymph nodes

• B cell

• Treg

• TH17

• TH2

• TH1

• CD8

  • found in secondary lymphatic organs

T cells

• recognize and bind antigens (epitopes) by highly specific receptors

• develop in bone marrow

• mature in thymus

• reside mostly in lymph and some circulation

• (intra)cellular immunity

T cell development

1. bone marrow

2. pro-T cells

3. differentiate in thymus

   • expression of T cell receptor

   • expression of CD4 and CD8

   • thymic selection

4. naive mature T cells

5. migrate to spleen and secondary lymphatic organs

T cell production and maturation

• developed from hematopoietic stem cells

• differentiate in red marrow → enter blood stream → thymus

• in thymus immature T cells = thymocytes

thymic selection

1. checks for development of functional T cell receptor (TCR)

   • if defective = apoptosis

2. determine is thymocyte interacts with MHC molecules

   • good = stimulation for further maturation

   • bad = apoptosis

3. removes self-reacting thymocytes (central tolerance)

   • reacts to self-antigens = apoptosis

   • self-reacting T cells in bloodstream cause autoimmune disease

mature naive T cell

T cells that have not been activated by antigen presenting cells (APC)

• have not encountered a pathogen

• 2% of thymocytes that survive thymic selection

T cell receptors

• membrane-bound glycoprotein

• resemble one-antigen binding arm (Fab fragment)

• 2 peptide chains that span cytoplasmic membrane

  • constant and variable region

• only recognize protein antigens

• after activation, no class switching, no secreted form

regions of hypervariability

• antigen-binding site of variable region

• hypervariable-loop regions called CDRs

• 3 on each chain: CDR1, CDR2, and CDR3

  • form only one binding-site

generation of T cell receptor diversity

• occurs in thymus

• somatic recombination creates diversity of immunoglobulins

• V(D)J recombinase with RAG identify RSSs

cluster of differentiation (CD)

naming system used to classify and differentiate leukocytes

• CD molecules are cell surface glycoproteins

  • important in classification of T cells

helper T cells (TH)

• CD4 surface molecule

• activated by APCs presenting antigens associated with MHC II

regulatory T cells (Treg)

• CD4 surface molecule

• activated by APCs presenting antigens associated with MHC II

cytotoxic T cells

• CD8 surface molecule

• activated by APCs or infected nucleated cells presenting antigens associated with MHC I

functional T cell receptor complex

• CD3 complex made of gamma, delta, and epsilon proteins

• upon antigen-binding: CD3 and zeta chain transmit signals to cell by associating with intracellular signaling molecules

antigen presentation

• professional APCs usually phagocytic (digest and present antigens)

• selects for most antigenic, immunodominant epitope, which will bind to MHC II

• PRESENTS PROTEIN ANTIGEN EPITOPES TO HELPER T CELLS

antigen-presenting cells (APCs) steps

1. ingests pathogen

2. digested into small antigen fragments

3. antigen combine with MHC

4. presented on MHC

antigen processing

1. pathogen protein in human cell

2. antigen processing by breakdown of protein

3. presentation of peptide by MHC molecule

4. recognition of antigen:MHC complex by T cell receptor

   • focuses on primary structure (peptides)

major histocompatibility complex (MHC)

collection of genes coding for MHC molecules found on surface of all nucleated cells of body

• MHC I: present normal self-antigens on all nucleated cells, signal WBC to initiate immune response

• MHC II: only found on macrophages, dendritic cells, and B cells

  • both can present abnormal or non-self pathogen antigens

  • not including RBCs

MHC class II processing of antigens

1. extracellular antigen

2. peptide production in phagolysosome

3. peptide binding by MHC class II

4. MHC class II presents peptide at cell surface

MHC class I processing of antigens

1. intracellular antigen (foreign particles)

2. antigen processing to peptides in proteasome

3. peptide transport into ER

4. peptide binding by MHC class I

5. MHC class I presents peptide at cell surface

APCs: macrophage, dendritic cells, and B cells

• all nucleated cells in body have mechanisms for making antigens that bind to a MHC molecules

• ONLY macrophages, dendritic cells, and B cells have ability to present antigens to activate T cells

• T cells cannot bind to antigens on pathogens directly without first being activated by APCs

MHC class I (CD8)

cytotoxic T cells: produce toxic agents to kill targets

MHC class II (CD4)

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

• regulatory T cells: suppress immune responses

interaction between MHC and CD receptors

each MHC is identified by a specific CD receptor on surface of T cells

• CD4 vs CD8

antigen presentation with MHC II molecules

• macrophages, dendritic cells, and B cells activate T cells

• select for most antigenic, immunodominant epitope, binds to MHC II

• epitope presented to HELPER T CELLS

antigen presentation

• T cell receptors recognize the epitope

• CD receptors recognize class of MHC

activation of helper T cell

• CD4 receptors on helper T cell surface recognize and speficially bind to MHC II on macrophage surface

• binding between helper T cell and APC activates helper T cell

activation of B cell

• receptor interactions with helper T cell and cytokines secreted by helper T cell activate B cell

• activated helper T cell interacts with specific MHC+antigen complex on surface of B cell

  • interaction causes helper T cell to secrete chemicals

antigen presentation with MHC I molecules

• healthy cells: proteins normally found in cytoplasm are degraded by proteasomes, processed into self-antigen and bind to MHC I

• infected with intracellular pathogen: protein antigens specific to pathogen are processed and bind to MHC I

• signals that infected cell must be destroyed along with pathogen