unit 4, lesson 4 , part 1 Adaptive Cellular Immunity & T Cells

• Lesson 4 focuses on adaptive cellular immunity.
• Adaptive cellular immunity involves B cells and T cells

Case Scenario: Rheumatoid Arthritis

• Pam, a 50-year-old woman, was diagnosed with Rheumatoid arthritis and is treated with Abatacept, a T cell inhibitor.
• Understanding the role of T cells in disease and the function of Abatacept is important in this case.

T Cells

• T cells are most effective in cell-to-cell interactions, targeting cells infected with viruses, bacteria, or intracellular parasites, as well as abnormal or cancerous cells and infused/transplanted foreign tissue.
• T cells recognize and respond to processed antigen fragments displayed by antigen-presenting cells (APC) via their T cell receptor (TCR).
• A T cell receptor recognizes an antigen in the form of a complex: peptide bound to an MHC molecule.
• The T-cell receptor is a heterodimer composed of two transmembrane glycoprotein chains, α and β chains, with extracellular portions containing two domains resembling immunoglobulin V and C domains.

TCR Antigen Recognition

• TCRs recognize processed antigen + peptide fragments (processed by antigen-presenting cells).
• Many antigens require variable TCRs.
• TCR repertoire involves somatic recombination that occurs physiologically in the assembly of the B cell receptor and T-cell receptor genes.
• Amino acid sequences in the antigen-binding regions of TCRs allow for the recognition of antigens from nearly all pathogens and "altered self cells".
• Peptides that bind TCRs and activate T cells are recognized only when bound to an MHC molecule, forming a peptide:MHC complex.

T Cell-Mediated Immune Response

• Needed for intracellular antigens, T cells mediate cellular adaptive immunity.
• CD4 cells (T4 cells) are primarily helper T cells (TH), including TH1/Th2, Th17, and Treg cells.
• CD8 cells (T8 cells) are cytotoxic T cells (Tc) that destroy cells harboring foreign antigens.
• Memory T cells retain the memory of previous infections.

CD4 and CD8 T Cells

• CD4 T cells carry the co-receptor protein CD4 and recognize antigens derived from intravesicular sources, binding to MHC class II on APCs and differentiating into CD4 T helper cells (TH1 and TH2).
  • TH1 effector cells help/activate macrophages and B-cell responses to intracellular parasites such as bacteria and viruses.
  • TH2 effector cells help/activate macrophages and B-cell responses to helminths and other extracellular parasites.
• CD8 T cells carry the co-receptor protein CD8 and can kill other cells, as they are cytotoxic T cells. -CD8 T cells recognize antigens derived from cytosolic sources, with TCR binding to MHC class I on APC/infected body cell, resulting in direct cell killing of virus-infected or cancer cells.

T Regs

• T Regs regulate or suppress other cells in the immune system to prevent excessive activation, controlling the immune response to self and foreign particles (antigens) and helping prevent autoimmune disease.
• Natural Tregs are characterized by expressing both the CD4 T cell co-receptor and CD25, with CD25 being a component of the IL-2 receptor.
• TGF-beta induces differentiation of naïve CD4+ into Tregs.
• Tregs suppress activation, proliferation, and cytokine production of CD4+ and CD8+ T cells, leading to self-regulation and shutting down immune responses.

Memory T Cells

• Memory T-cells differentiate from both CD4+ and CD8+ T-cells.
• They remember how to overcome an invader by ‘remembering' the strategy used to defeat previous infections.
• After infection, some cells become long-lasting memory cells (>20 years).
• Memory cells respond quickly to subsequent antigen exposures.

T Helper Cell (CD4) Functions

• CD4 T Cells, specifically Th1 cells, target intracellular parasites like bacteria and viruses.
• They activate antigen-presenting cells like macrophages by binding bacterial peptides presented on MHC class II molecules. CD4 T cells can also activate B Cells by doing the same, with B Cells acting as the APC.

Antigen Presenting Cells

• Antigen presentation is a process in which protein antigen is presented to lymphocytes as short peptide fragments associated with antigen-presenting molecules (MHC class I or II) on the surface of antigen-presenting cells (APCs).
• APCs are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells.
• Classical APCs include dendritic cells, macrophages, Langerhans cells, and B cells.
• Antigen-presenting cells are categorized as professional and non-professional.
• Professional antigen-presenting cells express MHC class II, specialize in presenting antigen to T cells, and are very efficient at internalizing antigens through phagocytosis or receptor-mediated endocytosis.
• Professional APCs efficiently process the antigen into peptide fragments and display them bound to a class II MHC molecule.
• Non-professional antigen-presenting cells express MHC class I molecules, and most nucleated cells in the body can present antigen to CD8+ cytotoxic T cells via MHC class I.

(CD8) Cytotoxic T Cell Killing

• Cytotoxic T cells (CD8) kill virus-infected cells by releasing cytotoxic granules and cytokines.
• Cytotoxic granules contain protein perforin (which punches holes) and granzymes (able to induce apoptosis).

Cytotoxic CD8 T Cells

• Cytotoxic CD8 T cells can recycle to kill multiple targets via serial killing.
• Each killing requires the same series of steps, including T cell receptor binding to MHC and directed release of proteins.

The Role of MHC Class I and II

• Cytotoxic T cells and regulatory T cells generally recognize target cells bearing antigens associated with MHC class I molecules found on the surface of all nucleated cells.
• Helper T cells recognize foreign antigens in association with MHC class II, which are normally found only on professional antigen-presenting cells.
• Examples of those cells are dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells.
• CD4 and CD8 are Co-receptors

MHC Class I

• MHC class I molecules are found on the cell surface of all nucleated cells.
• Cytotoxic T cells and regulatory T cells generally recognize target cells bearing antigens associated with MHC class I.

MHC Class I Antigen Presentation Pathway

• Pathogen-derived or self-proteins within the cytosol of antigen presenting cells (APCs) are enzymatically digested into peptides by proteasomes.
• Peptides are then transported into the endoplasmic reticulum (ER)
• Peptides bind to MHC class I molecules and are transported via the Golgi to the plasma membrane.
• The endogenous antigen presented by MHC class I will then be recognized by the CD8+ T cells.

MHC Class II

• In Bacterial infection, pathogen is taken up by phagocytosis via a Macrophage.

MHC Class II Antigen Presentation

• MHC class II molecules bind to peptides derived from proteins degraded by proteases in the endocytic pathway.
• Peptides bind to newly synthesized MHC class II molecules in specialized antigen-processing.

MHC Class I & II Polyrmophism

• Function: Bind pathogen derived peptide fragments and display on cell surface for recognition by T cells.
• Virus-infected cells are killed directly by cytotoxic T cells.
• Macrophages are activated to kill bacteria in intracellular vesicles.
• B cells are activated to produce antibodies that eliminate or neutralize extracellular pathogens.
• MHC genes are the most known, polymorphic genes: different alleles.
• MHC is polygenic: several MHC class I and II genes that encode for MHC proteins with a range of peptide-binding specificities
• MHC is polymorphic: there are multiple alleles of each gene.
• The particular combination of MHC alleles of an individual is their MHC haplotype.
• Each individual inherits a set of 6 genes from the mother, and a set of 6 genes from the father; all genes are therefore expressed.

T Cell Co-Receptors

• T cell activation is controlled by co-stimulatory and co-inhibitory receptors.
• The adaptive immune response starts when an antigen presenting cell (APC) recognizes a danger signal (virus, bacteria, damaged self...).
• This recognition induces the APC’s maturation, cutting the antigen into small peptides for presentation in a complex with MHC, and induction of ligands of costimulatory molecules.
• With the recognition of the peptide by the TCR of the specific T cell, & activation by costimulatory molecules (CD28), T cells proliferate and are fully activated.
• Activated T cells then express co-inhibitory receptors (CTLA-4, PD-1).

T Cell Inhibitor Drugs

• Abatacept, used for Rheumatoid arthritis, blocks CD28, a co-stimulatory molecule necessary for T cell activation.
• This blocks T cell activation, even if MHC is presented, which is useful in autoimmune diseases like RA.