T CELL MEDIATED IMMUNITY (Cell Mediated Immunity)

CELL MEDIATED IMMUNITY (CMI)

* Adaptive immune response based on antigen specific T cells

* Antigen specific T cells* CD8 (cytotoxic)* CD4 (helper)

* TH1* TH2

* Transfer to naïve recipient (operational definition)* Not with antiserum* Can with lymphoid cells (syngeneic donor and recipient)

* Mature naïve T cells must be activated by specific antigen in secondary lymphoid tissues

ACTIVATION OF NAÏVE T CELLS INTO EFFECTOR T CELLS

* Purpose of secondary lymphoid tissues* Sites for initiation of adaptive response

* Examples* Skin and soft tissues (SST) to regional lymph nodes

* Blood stream to spleen

* Respiratory mucosa to BALT and tonsils

* Gastrointestinal mucosa to Peyer’s patches (GALT)

* Dendritic cells important in SST infections* Immature

* Phagocytic and migratory from infection sites

* Mature* Interaction with T cells in 2nd lymphoid tissues

ACTIVATION OF NAÏVE T CELLS INTO EFFECTOR T CELLS

* Enter T cell zone of 2nd lymphoid tissue and encounter* Dendritic cells

* Macrophages

* Presentation of antigen* Activation into effector T cells

* Effector cells* Remain in 2nd lymphoid tissue (CD4 TH2)

* Travel to infection site (CD8 and CD4 TH1)

* No encounter with specific antigen* Re-circulation to bloodstream

HOMING OF T LYMPHOCYTES

* Homing* Movement of naïve T cells into secondary lymphoid

tissue or effector T cells to infection site

* Homing determined by* Chemokines

* CCL19 and CCL21

* Cell adhesion molecules (CAM’s)

MOVEMENT OF T CELLS BY INTERACTION OF CAM’S

* Interaction (contact) is mediated by* Cell adhesion molecules (CAM’s)

* Cell adhesion molecules (CAM’s)* On surface of leukocytes and target cells

* Work independently of antigen

* Direct specific cell to cell contact

* Classification based on* Structure

* CD nomenclature

CLASSIFICATION OF CAM’S ON STRUCTURAL BASIS

* Selectins* Surface of leukocytes and macrophages

* L selectin

* Initiates interaction with endothelial cells

* Vascular addressins* Surface of endothelial cells

* GlyCAM-1 and CD34

* Initiates interaction with leukocyte and macrophage selectins

CLASSIFICATION OF CAM’S ON STRUCTURAL BASIS

* Integrins* Glycoproteins on surface of leukocytes and

dendritic cells* Lymphocyte function associated antigen (LFA-1)

* Initiates strong binding to* Immunoglobulin superfamily molecules

* Intercellular adhesion molecules (ICAM’s)

* Strong binding allows T cells to squeeze between endothelial cells

CLASSIFICATION OF CAM’S ON STRUCTURAL BASIS

* Immunoglobulin superfamily molecules* Located on leukocytes, APC’s and endothelial cells

* CD2, ICAM-1, ICAM -2

* Initiates interaction with integrins

* Various roles in cell adhesion* Passage of T cells between endothelial cells

* LFA-1 to ICAM’s

* Interaction of T cells with APC’s

* CD2 to LFA-3

ACTIVATION OF NAÏVE T CELLS REQUIRES CO-STIMULATION

* Antigen presenting cells (APC’s) deliver both* Antigenic specific stimulation

* Co-stimulation

* Co-stimulation from professional APC’s* Dendritic cells, macrophages, B lymphocytes

* Co-stimulatory molecule is B7* B7 on APC’s binds to CD28 on T cells

CHARACTERISTICS OF PROFESSIONAL ANTIGEN

PRESENTING CELLS* Mechanism of antigen uptake

* Expression of MHC molecules

* Expression of B7

* Antigens presented

* Location in secondary lymphoid tissues

* Location in body

PHAGOCYTOSIS INDUCES CO-STIMULATORY ACTIVITY IN

MACROPHAGES

* Resting macrophages express* No B7

* Low level MHC II

* Degradation of bacteria in phagolysosome release molecules which stimulate expression of B7 and MHC II* Lipopolysaccharide

* Macrophages most commonly present antigens to CD4 T cells* Listeria monocytogenes avoids MHC II presentation

PHAGOCYTOSIS INDUCES MATURATION OF DENDRITIC

CELLS

* Immature dendritic cells present in skin and soft tissues

* High level of phagocytosis and no co-stimulatory activity

* Phagocytosis induces* Migration to lymphoid tissue* Maturation to mature dendritic cells

* Interdigitating reticular cells

* Expression of * B7, MHC I, MHC II, CCL18 and DC-SIGN

* Dendritic cells stimulate CD4 and CD8 T cell responses

ENDOCYTOSIS INDUCES B7 EXPRESSION IN B CELLS

* Immunoglobulin receptors on B cells selective bind soluble protein antigen from extracellular environment* Lipopolysaccharide

* Antigen / Immunoglobulin complex is internalized by* Receptor mediated endocytosis

* Complexes delivered to endocytic vesicles* Degraded into peptides and bound to MHC II* Expression of B7

* B cells present antigen to CD4 T cells

ANTIGEN ACTIVATION OF T CELL RECEPTOR COMPLEX INITIATES

INTRACELLULAR SIGNALING PATHWAYS

* Antigen binding transmits signal via CD3 and zeta proteins

* Transmitted signal activates* Receptor associated kinases (Fyn)

* Fyn leads to phosphorylation of ITAM’s

* Immunoreceptor tyrosine based activation motifs (ITAM’s)* Cytoplasmic tails of CD3 and zeta proteins

ANTIGEN ACTIVATION OF T CELL RECEPTOR COMPLEX INITIATES

INTRACELLULAR SIGNALING PATHWAYS

* ZAP-70 (cytoplasmic tyrosine kinase) binds to phosphorylated ITAM’s of zeta chain

* Co-receptors (CD4 and CD8), with associated tyrosine kinase (Lck), bind to MHC molecules

* Co-receptor binding to MHC allows Lck to phosphorylate and activate ZAP-70

PROLIFERATION AND DIFFERENTIATION OF ACTIVATED T

CELLS BY INTERLEUKIN-2

* Naïve T cells express low affinity IL-2 receptor consisting of beta and gamma chains only

* Activation of naïve T cells induces* Synthesis and secretion of IL-2

* Synthesis of IL-2 receptor alpha chain

* Alpha chain combines with beta and gamma chains to make high affinity IL-2 receptor

* IL-2 binds to receptor and initiates T cell proliferation

ANTIGEN RECOGNITION BY NAÏVE T CELLS IN ABSENCE OF CO-

STIMULATION

* Naïve T cell only activated by professional APC carrying specific peptide:MHC complex and co-stimulatory molecule

* T cell beomes anergic when it encounters APC carrying specific peptide:MHC complex without co-stimulatory molecule

* No effect on T cell which encounters APC carrying no specific peptide:MHC complex but has co-stimulatory molecule

EFFECTOR OPTIONS OF CD8 AND CD4 T CELLS FOLLOWING ANTIGEN

ACTIVATION

* CD8 committed to becoming cytotoxic effector cells

* CD4 T cells can differentiate along two pathways* TH1 (help with CMI)* TH2 (help with humoral immune response)

* Mechanisms of differentiation not well understood

* Most immune responses involve both TH1 and TH2

CD4 T CELL RESPONSE TO MYCOBACTERIUM LEPRAE

* Mycobacterium leprae is an intracellular pathogen, agent of leprosy and directs either TH1 or TH2 response

* Most effective immune response is mediated by TH1 cells

* Immune response mediated by TH1 cells results in* Tuberculoid leprosy

* Immune response mediated by TH2 cells results in* Lepromatous leprosy

Figure 6-21

ACTIVATION OF NAÏVE CD8 T CELLS TO CYTOTOXIC EFFECTOR CELLS

* Activation of naïve CD8 cells requires strong co-stimulation

* Dendritic cells provide strong co-stimulation* Express high levels of B7

* APC with sub-optimal co-stimulation require CD4 T cell help

* Naïve CD8 and CD4 cells must recognize specific antigen on on same APC

ACTIVATION OF NAÏVE CD8 T CELLS TO CYTOTOXIC EFFECTOR CELLS

* Mechanisms of CD4 help* CD4 effector T cells secrete cytokines stimulating APC

to increase level of B7

* Naïve CD4 T cells secrete interleukin-2 which stimlates CD8 cells

* Requirement for stronger co-stimulation of CD8 cells means activation only when evidence of infection certain

PERFORMANCE OF EFFECTOR T CELL FUNCTIONS

* Classification of molecules which perform functions* Cytokines

* Proteins made by cells and affect behavior of cells

* Autocrine action

* Paracrine action

* Produced by all effector T cells

* Cytotoxins* Proteins which kill target cells

* Produced by cytotoxic CD8 cells

CYTOTOXINS AND CYTOKINES OF T CELLS

* T cells are distinguished by* Cytokines and cytotoxins produced and the effects on immune

response

* CD4 T cells produce and act primarily through cytokines* Macrophage stimulating (TH1)

* B cell activating (TH2)

* CD8 T cells produce and act primarily through cytotoxins* Perforin and Granzymes

SELECTIVE KILLING OF INFECTED CELLS BY CD8 CYTOTOXIC T CELLS

* Cytotoxic CD8 kill by inducing apoptosis* Cells do not lyse or disintegrate but shrivel and shrink

* Pathways of Apoptosis* Formation of transmembrane pores allowing proteolytic

enzymes to enter* Perforin and granzymes cytotoxins

* Induction of apoptosis signal following cell-cell binding* Fas ligand (CD8 T cell) to Fas receptor (Target cell)

TH1 T CELLS AND MACROPHAGE ACTIVATION

* Macrophage activation* Enhancement of macrophage function against

intracellular pathogens by TH1 cells

* Phagosome fused more efficiently with lysosome

* Important with Mycobacteria

* Activation of macrophages requires 2 signals provided by TH1 cells* Interferon-gamma

* CD40 ligand

INTRACELLULAR PATHOGENS AND GRANULOMA FORMATION

* Mycobacteria can resist killing by activated macrophages resulting in formation of granulomas

* Granulomas* Localized inflammatory response characterized by

* Central core of infected macrophages surrounded by activated T cell

* Central core of granuloma* Macrophages fused into multinucleated giant cells surrounded by

large single macrophages (epithelioid cells)

* In tuberculosis, centers of large granulomas display cheese-like appearance* Caseation necrosis

TH2 T CELLS AND ACTIVATION OF B LYMPHOCYTES

* CD4 TH2 cells activate B cells which recognize same antigen* Cognate interaction

* Activation takes place in secondary lymphoid tissue* Mechanism

* TH2 cell receptor binds to peptide:MHC II complex on B cell

* TH2 cell synthesizes* CD40 ligand which binds to CD40 receptor on B cell

* Interleukin-4, interleukin-5, interleukin-6

* Stimulate proliferation and differentiation of B cells

KNOWLEDGE OF COGNATE INTERACTION IMPROVES VACCINE

DESIGN AND EFFICACY

* Vaccination of infants and young children against Haemophilus influenzae type b

* Haemophilus influenzae type b* Agent of invasive disease in children < 5 years

* Meningitis and epiglottitis* Prior to vaccine availability

* Morbidity of 1 in 200 children* Mortality of 5%

* Approximately 70% of cases in children < 18 months

* Major virulence factor is type b capsular polysaccharide

KNOWLEDGE OF COGNATE INTERACTION IMPROVES VACCINE

DESIGN AND EFFICACY

* 1980 vaccines consisted of* Purified type b capsular polysaccharide

* Protects children > 18 months

* 1990 vaccines consisted of* Purified type b capsular polysaccharide conjugated to

protein* ActHIB (Sanofi Pasteur)

* Tetanus toxoid

* HibTITER (Wyeth)

* Diphtheria CRM 197 protein

* Protects children > 2 months