Cell-Mediated Immunity

Cell-Mediated Immunity

• An adaptive immune response mediated by specific cells of the immune system

– Primarily T lymphocytes (T cells), but also macrophages and NK cells.

– Formally defined as immunity that can be transferred from one organism to another by lymphoid cells, but not by serum antibody.

T cells• Main coordinators and effectors of cellular

immunity

• Defined by their development in the thymus and the presence of a T-cell receptor (TCR) complex

T cells (continued)• Two main types:

1. CD4+: Stimulate other immune cells.2. CD8+ Cytotoxic T cells: Kill intracellularly-infected cells.

• Two major types of CD4+ T cells:1. TH1: Inflammatory T cells -- Stimulate macrophages and promote inflammatory responses.

2. TH2: Helper T cells -- Stimulate B-cells to produce antibodies.

(A third type, TH3, has recently been shown to promote IgA production.)

T cells develop in the thymusand undergo positive and negative selection

• Positive selection: T cells which can react to self MHC (major histocompatability complex) carrying peptides are allowed to live. Those that cannot undergo apoptosis (suicide).

• Negative selection: T cells that react strongly to self-antigens on MHC are eliminated.

• Only those T cells that can react to MHC, but do not bind strongly to self-antigens emerge as mature T cells from the thymus.

• Only about 2% of immature T cells make it through positive and negative selection.

T cell developmentT cell development in the thymus:

Cortex

Medulla

Immature double-negative T cells (CD8-, CD4-)

Immature double-positiveT cells (CD8+, CD4+)

Positive selection/negativeselection

CD8+ T cells CD4+ T cells

Mature T cells

The T cell Receptor• Similar in structure to Immunoglobulins (similar to a single Fab

fragment.• Composed of two glycoprotein chains (/ or /). Most mature T cells

have TCRs composed of an chain and a chain (they are called / T cells).

• Each chain has a constant region and a variable region, similar to an antibody light chain.

• A TCR recognizes a small(8-13 aa) peptide epitopedisplayed on MHC

chain chain

Epitope-binding site

Variable region

Constant region

Transmembrane region

TCR compared to ImmunoglobulinsSimilarities• Both have specific Antigen-binding region created by the variable regions of two

polypeptide chains.• Both display great potential for diversity via genetic recombination at the

genome level

Differences• A TCR is monovalent (has one binding site). An Ig is bivalent (has two binding

sites).• The TCR has no secreted form. It is always membrane-bound.• The TCR does not recognize free antigen. Antigen must be presented to a T cell

on an MHC molecule (next week).• There is no class switching for the TCR. Once made, the TCR does not change.

chain chain

Epitope-binding site

Variable region

Constant region

Transmembrane region

T cell Receptor Immunoglobulin

• The TCR only recognizes specific peptide/MHC complexes expressed on the surfaces of cells

• A TCR complex is composed of one heterodimeric TCR (ususally /), plus a 5-polypeptide CD3 complex which is involved in cell signalling for T cell activation.

• Each TCR is produced through genetic recombination and recognizes one small peptide epitope (about 8-13 amino acids).

• One T cell expresses only one specific type of TCR.

The T cell Receptor, cont.

CD3 is the activation complex for the TCR

Binding of antigen/MHC to the TCRstimulates CD3. CD3 then sends an activation signal to the inside of theT cell.

TCR: Antigen recognition

CD3CD3

Cell signaling

Responses to infection -- T cell component

Infection

Infection

Infection

Infection

Infection

Innate immunity(0-4 hours)

Early inducedresponse

(4-96 hours)

Late adaptiveresponse

>96 hours)

Protective immunity

Immunologicalmemory

Recognition bypre-formed, non-specific effectors

Recruitment ofeffector cells

Transport ofantigen to

lymphoid organs

Recognition bypre-formed, Ab

and T cells

Recognition bymemory B cells

and T cells

Removal ofinfectious agent

Removal ofinfectious agent

Removal ofinfectious agent

Removal ofinfectious agent

Removal ofinfectious agent

Recognition andactivation ofeffector cells

Recognition by naïve

B and T cells

Clonal expansionand differentiation

to effector cells

Rapid expansionand differentiation

to effector cells

This chart is not intended to be memorized

The adaptive immune response involving antigen-specific T cells and B cells is only one part of the immune response and is required to protect against pathogens. A pathogen is by definition an organism that can cause disease. In other words, a pathogen is an organism that can bypass innate immunity and requires an adaptive immune response for clearance.

Generation of an adaptive immune response

• During an adaptive immune response,T cells which recognize specific antigen(s) are selected for differentiation into armed effector cells which undergo clonal expansion to produce a battery of antigen- specific cells.

• Clonal expansion refers to the process by which antigen-specific T cells or B cells are stimulated to reproduce clones of themselves to increase the system’s repertoire of antigen-specific effectors.

Generation of an adaptive immune response

• Activation of antigen-specific T cells (the initiation of the adaptive response) occurs in the secondary lymph tissues (lymph nodes and spleen).

• This activation depends upon antigen presentation by a professional antigen presenting cell (APC) along with simultaneous co-stimulation. (eg., B7 on the APC, CD28 on the T cell).

Initiation of the adaptive immune response

• The first step is the draining of antigen into the lymph node(s).• In the lymph node(s) (or spleen), antigens are trapped by

professional APCs which display them to T cells.

The antigen presenting cells, continued

Dendritic Cell

Macrophage B cell

Note: this B cell is not a plasma cell -- a plasma cell is shown above. Plasma cells do not present antigen. They simply pump out antibody for a few days then die.

T cells continuously circulate via the blood and lymph through different lymph nodes until they either find presented antigen or eventually die • When a T cell encounters an APC displaying antigen to which

it can bind, it stops migrating and binds strongly to the APC.• Within about 2 days (48 hours), most antigen-specific T cells

have been trapped by antigen and within about 4 to5 days armed effector T cells are migratingout of the lymph node.

Review -- Cytokines produced early in response to infection influence the future functions of activated CD4+ cells

TH0

TH2TH1

IL-2IL-4IFN-

IL-2IFN-F

IL-4IL-6IL-10

• Cytokines produced by TH1 cells inhibit TH2 cells

• Cytokines produced by TH2 cells inhibit TH1 cells

• An immune response is often dominated by a cell-mediated response or an antibody response.

• Some pathogens have evolved strategies to shift the immune response toward the less effective type for that pathogen.

Functions of the different T cell types• CD8+ cells: Kill virally

infected cells• CD4+ cells:

– TH1: Activate macrophages to aggressively ingest antigen and to kill ingested microbes.

– TH2: Stimulate B cells to differentiate into antibody-producing plasma cells. B cells will only undergo isotype switching after receiving T cell help. The Ig class that a B cell switches to is specified by the types and balance of cytokines secreted by the helper T cell.

Immunological memory

• When B cells are activated to reproduce, some differentiate into plasma cells and some become long-term memory cells.

• An adaptive immune response also produces T cell memory, but the nature of memory T cells is unknown. Two possibilities exist. Memory T cells probably originate from either:– 1. A long-lived subset of effector T cells that differentiates into

memory T cells -- like memory B cells.– 2. The continuous low-level activation of naïve T cells by specific

antigen that is retained in the lymph nodes after an infection. This mechanism would suggest that APCs in the lymph node hold on to antigen on a long-term basis after an infection and continuously stimulate T cells at a low level so there is always a small effector population ready to go.

MHC classes I and IIFunctions:• class I MHC:

– Displays peptides derived from antigen originating inside the cell (endogenous antigen).

– Important in cytotoxic responses (eg, CD8+-killing of virus-infected cells).• Class II MHC:

– Displays antigen derived from ingested antigens (exogenous antigen).– Important in humoral (antibody) responses as well in fighting as some

intracellular parasites (eg. Mycobacterium tuberculosis and M. leprae)

• Locations:– Class I MHC found on all nucleated cells (all cells need to be prepared to be

killed in case of a viral take-over or tumorigenic transformation).– Class II MHC found only on antigen presenting cells (cells that present antigen

to CD4+ T cells --> Macrophages, activated B-cells, dendritic cells.

Antigen Presentation to T cells: MHC

• Antigens are presented to T cells as short peptide fragments bound to Major Histocompatibility (MHC) molecules.

• Two types of MHC in humans and mice:– MHC I: presents an 8-10 amino acid peptide to CD8+ T

cells.– MHC II: presents a longer peptide (13 aa or more) to CD4+

T cells.

MHC structure

Peptide binding cleft

1

2 2

1

Class II MHC

Peptide binding cleft

12

3 2-microglobin

Class I MHC

• MHC classes I and II have an almost identical 3-D structure.• Both classes of MHC are polygenic (each cell has many MHC

genes) and polymorphic (there are many alleles for each locus), but the MHC genes do not undergo recombination.

Note: Human MHC are called HLA (human leukocyte antigen).

MHC / T cell interactions

• The MCH/peptide-TCR interaction is facilitated by the CD4 or CD8 co-receptor.

Class II MHCClass I MHC

TCR complex

CD8

CD8+ T cell

target cell

CD4

Antigen presenting cell

TCR complex CD4+ T cell

Antigen processing: Endogenous pathwayAll nucleated cells can process endogenous proteins and present fragments on their class I MHC.

Endoplasmic reticulum

Nucleus

Cytoplasmicproteins

degradation

Vesicle carryingMHC I-peptide

Processing in E.R. and complexing with MHC I

Display of MHC I + peptideon cell surface

Antigen processing: Exogenous pathwayProfessional antigen presenting cells ingest microbes and free particles, degrade them in lysozomes, and present fragments to CD4+ T cells on MHC II.

Endoplasmic reticulum

Nucleus

Vesicle carryingMHC II

MHC II is assembled in ER

Display of MHC II + peptideon cell surface

Ingestion of microbe

Degradtion in lysozome

Vesicle fusion, assembly of

peptide/MHC II

CD4+ T cell activation

• T cells require co-stimulation for activation -- binding of the TCR to MHC/peptide is not enough to activate a T cell by itself.

• B7 on an APC binds to CD28 on the T cell to deliver a co-stimulatory signal. (see figure 13-8).

• Activation by peptide/MHC-TCR binding plus a co-stimulatory signal leads to Interleukin-2 (IL-2) release and up-regulation of the IL-2 receptor on the T cell.

• IL-2 stimulates growth and proliferation of T cells.

CD8+ T cell activation

• A naïve circulating CD8+ T cell also requires co-stimulation to become an “armed” effector cell.

• A CD8+ T cell can be activated by an APC displaying MHC I/peptide along with B7 (CD8+ cells also have CD28).

• Activation of the CD8+ cell causes upregulation of the IL-2 receptor and production of IL-2, leading to growth and proliferation.

• An activated CD8+ T cell can sustain itself on its own IL-2 production, once activated.