T Cells and Adaptive Immunity

• Lesson 4 is about adaptive cellular immunity involving B cells and T cells

T Cells

• T cells mature and differentiate in the thymus, originating as lymphocytes from red bone marrow.
• T cells are best suited for cell-to-cell interactions, targeting cells infected with viruses, bacteria, intracellular parasites, abnormal/cancerous cells, or infused/transplanted foreign tissue.
• T cells recognize processed antigen fragments displayed by antigen-presenting cells (APCs) via their T cell receptor (TCR).
• A T cell receptor recognizes antigen in a peptide bound to an MHC molecule.
• The T-cell receptor is a heterodimer of two transmembrane glycoprotein chains called alpha and beta chains.
• The extracellular portion of each chain has two domains resembling immunoglobulin V and C domains.

TCR Antigen Recognition

• TCRs recognize 'processed' antigen peptide fragments that are processed by antigen-presenting cells.
• Many antigens require many variable TCRs.
• TCR repertoire utilizes somatic recombination, which occurs assembling the B cell receptor and T-cell receptor genes through V(D)J recombination.
• Amino acid sequences in the antigen-binding regions of TCRs allow recognition of antigens from nearly all pathogens, including bacteria, viruses, parasites, and altered self-cells in cancer.
• 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

• T cells mediate cellular adaptive immunity, needed for intracellular antigens.
• CD4 cells (T4 cells) are primarily helper T cells called TH cells and include TH1/Th2, Th17 cells and Treg cells
• CD8 cells (T8 cells) are cytotoxic T cells (Tc) that destroy cells harboring foreign antigens.
• Memory T cells are also part of the T cell-mediated immune response.

CD4 and CD8 T Cells

• CD4 T cells carry the co-receptor protein CD4.
• CD4 T cells recognize antigens derived from intravesicular sources.
• TCR binds to MHC class II on APCs.
• CD4 T cells differentiate into CD4 T helper cells, including TH1 and TH2 effector cells that differ by the immune response type that they produce.
• Th1 cells target intracellular parasites such as bacteria and viruses.
• Th2 cells target helminths and other extracellular sources.
• CD8 T cells carry the co-receptor protein CD8 and can kill other cells, known as cytotoxic T cells.
• CD8 T cells recognize antigens derived from cytosolic sources.
• The TCR binds to MHC class I on APC/infected body cells.
• CD8 T cells cause direct cell killing by killing virus-infected and cancer cells.

T Regulatory Cells (Tregs)

• Tregs regulate or suppress other cells in the immune system to prevent excessive activation by controlling the immune response to self and foreign antigens, also helping prevent autoimmune disease.
• Natural Tregs express both the CD4 T cell co-receptor and CD25.
• CD25 is 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.
• Tregs help shut down immune responses after successful elimination for self-regulation.

Memory T Cells

• Memory T-cells differentiate from both CD4+ and CD8+ T-cells, remembering how to overcome invaders from defeating previous infections.
• Following infections that lymphocytes has recognised antigens, it expands to eliminate the infection and some then become long lasting memory cells.
• Memory cells respond very quickly to subsequent exposure to antigens.

T Helper Cell (CD4) Functions

• Th1 cells target intracellular parasites such as bacteria and viruses.
• The CD4 T cell binds bacterial peptide presented by MHC class II on a macrophage cells, activating the APC.
• The CD4 T cell also binds antigenic peptide presented by MHC class II displayed on a B Cell, activating the APC which is B cell.

Antigen-Presenting Cells (APCs)

• Antigen presentation is a process where protein antigens are presented to lymphocytes as short peptide fragments.
• These fragments are associated with antigen-presenting molecules, such as MHC class I or MHC class II on the surface of APCs.
• APCs are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by T cells.
• Classical APCs include dendritic cells, macrophages, Langerhans cells, and B cells.
• APCs fall into two categories: professional and non-professional.
• Professional APCs 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 antigens into peptide fragments and display those peptides bound to a class II MHC molecule Non-professional APCs express MHC class I molecules, and most nucleated cells in the body can present antigen to CD8+ cytotoxic T cells via MHC class I

Cytotoxic T Cells (CD8) Kill Virus-Infected Cells

• Cytotoxic killing occurs by releasing cytokines and cytotoxic granules.
• Cytotoxic granules are comprised of the following:
  • Protein Perforin punches holes in the target-cell membrane, similar to the membrane attack complex of complement.
  • Granzymes induce apoptosis.
• Fas/FasL induces apoptosis and eliminates immune effector cells during the contraction phase at the end of an immune response.
• CD8 T cells recognize and bind infected cells with antigens presented via MHC class I.

Cytotoxic CD8 T Cells Induce Apoptosis in Target Cells

• Cytotoxic T cells can recycle to kill multiple targets through serial killings.
• Each killing requires binding the T cell receptor to MHC and directed release of the following proteins:
  • Perforin polymerizes to form a pore in the target membrane.
  • Granzymes, which are serine proteases, get released to activate apoptosis inside the target cell by cleaving the proteins and shutting down the production of viral proteins.

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.
• MHC class I molecules are found on the cell surface of all nucleated cells.
• Helper T cells recognize foreign antigens in association with MHC class II.
• MHC class II molecules are normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells.
• Co-receptors CD4 and CD8 are also involved.

MHC Class I Presentation

• MHC class I molecules are found on the cell surface of all nucleated cells.
• In virus-infected cells, viral proteins are synthesized in the cytosol and peptide fragments of viral proteins are bound by MHC class I in the endoplasmic reticulum.
• Bound peptides are transported by MHC class I to the cell surface and are recognized by cytotoxic T cells and regulatory T cells bearing antigens for MHC class I molecules

MHC Class I Antigen Presentation Pathway

• Pathogen-derived proteins that are present in the cytosol of antigen presenting cells (APCs) are processed inside proteasomes.
• The processed peptides go into the endoplasmic reticulum (ER).
• Inside the ER, these peptides are loaded onto newly synthesized MHC class I molecules and transported via the Golgi to the plasma membrane to be presented to the CD8 cells.

MHC Class II Presentation

• During bacterial infections, the pathogen is usually taken up by phagocytosis in marophages to be presented to the CD 4 cells.
• In B cells, the antigen binds to the surface receptor BCR and the antigen-BCR complex gets endocytosed and is degraded to form peptide fragments.
• MHC class II molecules then binds to the degraded peptides and is transported to the cell surface for presentation to the CD 4 T cells.

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 compartments.

MHC Class I & II Polymorphism

• The function is to bind pathogen-derived peptide fragments and display them on the cell surface for recognition by T cells.
• The consequence of this is that virus-infected cells are killed directly by cytotoxic T cells, macrophages are activated to kill bacteria in intracellular vesicles, and B cells are activated to produce antibodies to eliminate/neutralize extracellular pathogens.
• MHC is polygenic, meaning several MHC class I and II genes encode MHC proteins with a range of peptide-binding specificities.
• MHC is polymorphic, meaning there are multiple alleles of each gene.

MHC Haplotype

• Each individual inherits a particular combination of MHC alleles, called a MHC haplotype.
• Each individual inherits a set of 6 genes from the mother and 6 from the father, and all genes are expressed therefore.
• There are 6 MHC class I genes and 6 MHC class II genes.

Siblings and MHC Haplotypes

• Siblings have a one in four chance that they will share the same haplotype.

T Cell Co-Receptors

• T cell activation is controlled by co-stimulatory and co-inhibitory receptors.
• In the beginning of adaptive immune response, the antigen presenting cell (APC) recognizes danger signals, such as a virus, bacteria or damaged self.
• This recognition induces the maturation of the cell, and antigen is cut into small peptides for presentation in complex with MHC.
• In addition, it leads to the induction of ligands if costimulatory molecules, such as CD80.
• All of this allows the recognition of the peptide by the TCR of the specific T cells which is then activated via costimulatory molecules (CD28).
• Activated T cells then express co-inhibitory receptors (CTLA-4, PD-1).

T Cell Inhibitor Drugs

• Abatacept is a treatment for rheumatoid arthritis blocks the co-stimulatory molecule that is necessary for T cell activation (CD28), blocking T cell activation even if MHC is presented.
• This is applied in cases of active T cells towards self antigens as a treatment to autoimmune diseases like RA.