Cell mediated immune response

Immune Response II

DR. SUFI H. Z. RAHMANMBBS, MD (IMMUNOLOGY)

LECTURER, MEDICAL FACULTY, AUCMS

Objectives

◆Role of antigen presenting cells in cellular immune response

◆Role of lymphocytes in cellular immune response

◆Mechanisms involved in cellular immune response

◆Types cytokines and their role in cellular immune response

◆Interaction between the components of the immune system in regulating immune response

Cell Mediated Immunity

◆Provided by T lymphocytes◆Provides immunity to (i) intracellular bacteria (ii) viruses, (iii) fungi, (iv) protozoa and (v) tumours

◆T cells can recognize antigen only when it is presented on the surface of Antigen presenting cells (APCs) by self MHC molecules

◆This self MHC restriction results from positive selection during maturation of T cells in the thymus

Antigen Presenting Cells

◆Cells that present antigens to T lymphocytes and activate them

◆Express both Class I and Class II MHC molecules on surface

◆Also express B7 (B7.1 and B7.2) molecules◆Present antigens by Class I MHC molecules to CD8+ T cells and by Class II MHC molecules to CD4+ T cells

◆Professional APCs are Dendritic cells, Macrophages and B cells

Antigen Presenting Cells

Antigen Presentation

APCs process and present antigens in two pathways

1. Exogenous or Endocytic pathway: Phagocytosed microorganisms are degraded in the phagosomes and peptides are presented in this pathway by Classs II MHC molecules

2. Endogenous or Cytosolic pathway: Intracellular microorganisms synthesize protein in the cytoplasm that are presented in this pathway by Class I MHC molecules

Antigen Presentation

◆Derived from bone marrow by haematopoiesis

◆Progenitor T (Pro- T) cells migrate to thymus

◆Maturation occurs in the thymus• Rearrange TCR gene segments and acquire TCR • Undergo two selection process

Positive selection: Self MHC restriction Negative selection: Self tolerance

• Acquire surface CD molecules e.g. CD3, CD4/ CD8

◆Two population of T cells are released to the circulation:• CD4+ or helper T (TH) cells• CD8+ or Cytotoxic T (TC) cells

T lymphocytesMaturation

Maturation of T

lymphocytes in the

Thymus

e

T lymphocytesMaturation

Mechanism of CMI

APCs present antigens by Class I MHC molecules to CD8+ (TC) cells and by Class II MHC molecules to CD4+

T (TH) cells

TCB7 CD28

Antigen recognition by T cells

◆T cells recognize specific antigens presented with MHC molecules on the surface of APCs by TCR

◆Each T cell has 105 TCRs on its surface all of which recognize a one antigen (or epitope)

◆1010 clones of T cells will recognize 1010 antigens


Mechanism of CMI

◆Antigen recognition by TCR provides Stimulatory signal (Signal 1) to the T cell

◆Binding of B7 molecule on APC with CD28 molecule on T cell provides Co-stimulatory signal (Signal 2) to the T cell


Mechanism of CMI

◆When T cells receive both Stimulatory (Signal 1) and Co-stimulatory (Signal 2) signals they are activated (clonal activation)

◆If the T cells receive only the Stimulatory signal without Co-stimulatory signal, they are permanently inactivated (clonal anergy)

Stimulatory signal+ Costimulatory signal= Activation

Stimulatory signal without Costimulatory signal= Anergy

T cell

T cell

T cell activation

Mechanism of CMI

◆Activated T cells start to proliferate, synthesize and secrete IL-2 and express IL-2 receptors on cell surface

◆After several divisions they differentiate to effector and memory T cell populations

◆Memory T cells have long life span (20- 30 years) and provide immunity if the person is re-exposed to the same antigen

T cell differentiation

Mechanism of CMI

Effector T cells are short-lived (few days to weeks) cells and carry out specialized functions e.g. • CD8+ effector T cells: Induce apoptosis of virus infected and tumour cells (Cytotoxic killing)• CD4+ effector T cells: Secrete cytokines that cause macrophage activation to kill intracellular pathogens and to help TC cell and B cell activation

T cells differentiation

Mechanism of CMI

Antigen Elimination by CMI

Cytotoxic T cells induce apoptosis of infected

cells bearing antigen on the surface

CD8+ Effector T cells


◆ With influence of cytokines e.g. IL- 12 from APCs, TH cells differentiate to TH1 cells

◆ TH1 cells release cytokines e.g. interferon- g (IFN- g)

◆ IFN-g activates macrophages that phagocytose and eliminate intracellular pathogens



Activated macrophages have more phagocytic and killing activity and they phagocytose and kill

intracellular pathogens effectively


Naïve cytotoxic T cells (cytotoxic T cell precursor) require cytokines from TH cells for activation

TH cells help TC cell activation

Regulatory role of TH cells

Activation of naïve B cells require

◆Direct interaction with TH

cells by• Antigen in Class II MHC and TCR• CD40 and CD40L • B7 and CD28

◆Cytokines from TH cells

TH cells help B cells

TH cells help B cells to induce humoral immune response

Regulatory role of TH cells

Regulatory Role of TH cells

◆ Cytokines from TH1 cells also help TC cell activation

◆ Thus TH1 cells regulate CMI

◆ With the influence of IL-4 (from mast cells?) TH cells differentiate to TH2 cells

◆ Cytokines from TH2 cells help B cell activation

◆ Thus TH2 cells regulate humoral immunity

4a. Activated T cells differentiate to

effector T cells and memory T cells

(macrophages)

Interaction between the components of the immune system

CD4+ T (TH) cells regulate the function of both TC and B cells

TH cell activation by Superantigens

◆Superantigens are viral or bacterial proteins that bind simultaneously to the Vb domain of a TCR and to the a chain of class II MHC molecule

◆They bind outside of the TCR antigen binding cleft

◆Any T cell expressing a particular Vb sequence will be activated by a corresponding superantigen

◆Hence, the activation of TH cells by superantigens is polyclonal and can affect a huge number TH cells

◆It results in overproduction of cytokines from TH cells (e.g. IL-2) and from macrophages (e.g. IL-1, TNF)

◆Huge amount of cytokines produce toxic systemic effects e.g. shock, vomiting, diarrhoea, organ failure etc. rather than providing immunity

◆Super antigens are usually soluble proteins secreted by bacteria (exogenous) but may be membrane bound proteins of some viruses (endogenous)


Superantigen Disease

Enterotoxin of Staphylococcus aureus

Food poisoning

Toxic shock syndrome toxin (TSS1) of Staphylococcus aureus

Toxic shock syndrome

Exfoliative dermatitis toxin of Staphylococcus aureus

Scalded skin syndrome

Erythrogenic toxin of Streptococcus pyogenes

Scarlet fever

Pyrogenic toxin of Streptococcus pyogenes

Streptococcal Toxic shock syndrome

Mycoplasma arthritidis supernatant

Arthritis, Shock


Cytokines

◆ Protein molecules secreted by cells that regulate function of that cell or other cells

◆ The name denotes their role in cell to cell communication

◆ Development of an effective immune response involves lymphocytes and other leukocytes

◆ Cytokines play key role in the complex interaction between cells of the Immune system

Cytokines

◆ Autocrine: Acts on the same cell that secretes it

◆ Paracrine: Acts on adjacent cells

◆ Endocrine: Carried by the blood or body fluid to a distant site and acts on distant cells

Cytokines

◆ One cytokine may act on various cells and produce various effects

◆ Many cytokines may act on the same cell and produce same effect

◆ One cytokine may increase action of the other

◆ One cytokine may inhibit action of the others

Cytokines

◆ Cytokines secreted by some leukocytes and acting on other leukocytes are called interleukins

◆ Cytokine secreted by lymphocytes are called lymphokines

◆ Cytokines secreted by monocytes and macrophages are sometimes called monokines

◆ Cytokines that cause chemotaxis of leukocytes are called chemokines

Cytokines

Further Review

◆Levinson W. Review of Medical Microbiology and Immunology. 11th edition. McGraw Hill, 2008.◆Kindt TJ, Goldsby RA, Osborne BA. Kuby Immunology. 6th ed. WH Freeman, 2006.◆Abbas AK, Lichman AH. Basic Immunology. 3rd edition. Elsevier, 2011.

Health & Medicine

Cell mediated immune response