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Lecture outline. Signals for T cell activation Costimulation and the B7:CD28 family Responses of T cells Cytokines . The life history of T lymphocytes. c. Abbas, Lichtman and Pillai . Cellular and Molecular Immunology, 7 th edition, 2011 . Elsevier.

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Lecture outline
Lecture outline

  • Signals for T cell activation

  • Costimulation and the B7:CD28 family

  • Responses of T cells

  • Cytokines


The life history of T lymphocytes

c

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011

Elsevier


Principles of lymphocyte activation

  • Lymphocytes are normally in a resting state in lymphoid organs and circulation

  • Rapid response to antigen (activation) --> proliferation, change to functionally active effector cells (differentiation)

  • Migration to tissues, where they perform their function of eliminating infections

  • Multiple possible steps for therapeutic targeting



Recognition of antigen by the TCR

The TCR of CD4+ and CD8+

T cells recognizes MHC-bound peptide + portions of the MHC.

Other T cells (gd T cells, NKT cells) recognize non-peptide antigens; these are small cell populations whose function is unclear.


Antigen recognition by T cells

  • Each T cell sees a (self) MHC molecule and a bound peptide

    • Dual recognition determines specificity and MHC restriction

  • Multiple ligands on APCs and receptors on T cells, in addition to the TCR, participate in orchestrating responses to antigens

  • Signaling: clustering of receptors --> activation of kinases (often via “adaptor proteins”) --> activation of transcription factors


Receptor-ligand pairs involved in

T cell activation

Different molecules involved in T cell responses to

antigen serve distinct functions, seen even in this partial listing.

Drugs that block these ligand-receptor pairs have been developed

to treat immune-mediated inflammatory diseases, graft rejection.


Molecules involved in T cell activation

  • Signal transduction

    • CD4 and CD8 co-receptors recognize MHC molecules (class II or class I) at the same time as the TCR sees the peptide-MHC; CD4 and CD8 provide necessary activating signals for T cells

    • CD28 is a receptor for “costimulators” expressed on APCs


Molecules involved in T cell activation

  • Signal transduction

    • CD4 and CD8 co-receptors recognize MHC molecules (class II or class I) at the same time as the TCR sees the peptide-MHC; CD4 and CD8 provide necessary activating signals for T cells

    • CD28 is a receptor for “costimulators” expressed on APCs

  • Strengthen adhesion with antigen-presenting cells

    • Integrins function as adhesion molecules

    • Affinity of integrins is increased by chemokines produced during inflammation, and by antigen recognition by TCRs

  • Control routes of T cell migration

    • Selectins and integrins control migration of naïve T cells through lymph nodes and of effector and memory T cells to sites of infection

  • Therapeutic targets


Formation of the immunological synapse

Signaling molecules orient to one region of the cell within seconds of antigen recognition


Therapeutic targeting of molecules involved in T cell responses

  • CD3: signaling molecule attached to the TCR on all T cells; anti-CD3 MAb to deplete T cells (transplants)

  • Integrins (LFA-1, VLA-4, others): adhesion to APCs, endothelium; anti-integrinMAb’s to block leukocyte migration into tissues

  • “Costimulators”: CD28, others; costimulatory blockade


The responses two-signal requirement for lymphocyte activation

Costimulation: signal(s)

in addition to antigen that are needed to initiate adaptive immune

responses

Best defined for CD4+ T

cells

Multiple pairs of ligands

on APCs and receptors

on T cells may serve this

function; best defined

are the B7-CD28 families of proteins

c

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011

Elsevier


Two signal requirement for T cell activation responses

  • Naïve lymphocytes need two signals to initiate their responses

  • Signal 1: antigen recognition

    • Ensures that the response is antigen-specific

  • Signal 2: costimulators induced on APCs during infection (or upon recognition of necrotic cells)

    • Ensures that the immune system responds best to microbes (or dangerous insults, such as tumors) and not to harmless antigens

    • Adjuvants stimulate expression of costimulators



The B7: CD28 family responses

Different members

of the B7-CD28

families serve

different roles in

stimulating and suppressing

immune responses.


Major functions of selected B7-CD28 family members responses

  • B7-CD28: initiation of immune responses

  • ICOS-ICOS-L: role in B cell activation in germinal centers

  • B7-CTLA-4: inhibits early T cell responses in lymphoid organs

  • PD-1:PD-L1,2: inhibits effector T cell responses in peripheral tissues


APC responses

The opposing functions of CD28 and CTLA-4

B7

CD28

B7-CD28

interaction

Naïve

T cell

TCR

Proliferation,

differentiation

CTLA-4

B7-CTLA-4

interaction

Functional

inactivation

Inhibitory pathways function normally to prevent

responses to self antigens: demonstrated by the

finding that blocking or eliminating these inhibitors

(CTLA-4, PD-1) causes autoimmune disease


Blocking CTLA-4 promotes tumor rejection responses

Tumor recognition by T cells leads to engagement of CTLA-4 on the T cells and inhibition of immune responses. Blocking CTLA-4 increases anti-tumor response and leads to tumor rejection.


Inhibitory role of PD-1 in a chronic infection responses

Virus-specific

T cell response

Residual virus

In a chronic viral infection in mice, recognition of virus by specific T cells leads to PD-1 engagement, inhibition of T cell responses, and persistence of the virus. Blocking the PD-1 pathway releases the inhibition, enhances the T cell response, and leads to viral clearance.


Inhibitory receptors responses

  • Prevent reactions against self antigens

  • Mediate immunosuppression in chronic infections (HCV, HIV)

  • Limit responses to tumors

  • Similar roles are established for both CTLA-4 and PD-1


The balance between activation and inhibition responses

  • How does a T cell choose to use CD28 to be activated or CTLA-4 to shut down?


The balance between activation and inhibition responses

  • How does a T cell choose to use CD28 to be activated or CTLA-4 to shut down?

    • Low B7 (e.g. when DC is displaying self antigen) --> engagement of high-affinity CTLA-4

    • High B7 (e.g. after microbe encounter) --> engagement of lower affinity CD28

  • Not well understood for the PD-1 pathway


Therapeutics based on the B7:CD28/CTLA-4 family responses

1. Costimulatory blockade

CTLA-4.Ig is used for diseases caused by ….?


Therapeutics based on the B7:CD28/CTLA-4 family responses

1. Costimulatory blockade

CTLA-4.Ig is used for diseases caused by excessive

T cell activation -- rheumatoid arthritis, graft rejection; not yet approved for IBD, psoriasis


Therapeutics based on the B7:CD28/CTLA-4 family responses

2. Inhibiting the inhibitor

Anti-CTLA-4 antibody is used for ….?


Therapeutics based on the B7:CD28/CTLA-4 family responses

2. Inhibiting the inhibitor

Anti-CTLA-4 antibody is approved for tumor

immunotherapy (enhancing immune responses against tumors)

Even more impressive early clinical trial results with anti-PD-1 in cancer patients


Costimulation responses

  • Required for initiating T cell responses

    • Many proteins on APCs and their receptors on T cells shown to “costimulate” (function with antigen to activate T cells); most important costimulators are B7:CD28

  • Ensures that T cells respond to microbes (the inducers of costimulators) and not to harmless antigens

    • Source of costimulation in responses to tumors and transplants: products of dead cells?

  • Therapeutic targets


Clonal responses

expansion

106

Contraction

(homeostasis)

# of microbe-specific T cells

CD8 cells

104

Memory

CD4 cells

102

7

14

200

Infection

Days after infection

T cell expansion and contraction (decline)

Many aspects of T cell responses and functions are mediated

by cytokines: initial activation -- IL-2; maintenance of memory cells -- IL-7; effector functions -- various


Cytokines responses

  • Secreted proteins that mediate immune and inflammatory reactions, and communications among leukocytes and other cells

  • Produced transiently in response to extrinsic stimuli

  • Bind to high-affinity receptors on target cells

  • Actions are most often autocrine and paracrine, rarely endocrine

  • Cytokines are pleiotropic (one cytokine has multiple actions) and redundant (different cytokines have similar actions)


Role of IL-2 and IL-2 receptors in T cell proliferation responses

Production of IL-2 and expression of high-affinity IL-2 receptors

are both dependent on antigen recognition + costimulation


Clonal expansion (proliferation) of T cells responses

  • Stimulated mainly by autocrine IL-2

    • T cell stimulation by antigen + costimulators induces secretion of IL-2 and expression of high-affinity IL-2 receptors

    • Therefore, antigen-stimulated T cells are the ones that expand preferentially in any immune response, keeping pace with replicating microbes


Clonal expansion proliferation of t cells
Clonal expansion (proliferation) of T cells responses

  • Stimulated mainly by autocrine IL-2

    • T cell stimulation by antigen + costimulators induces secretion of IL-2 and expression of high-affinity IL-2 receptors

    • Therefore, antigen-stimulated T cells are the ones that expand preferentially in any immune response, keeping pace with replicating microbes

  • CD8+ T cells may expand >50,000-fold within a week after an acute viral infection with minimal expansion of cells not specific for the virus (up to 10% of all CD8+ T cells in the blood may be specific for the pathogen)

  • Some of the progeny of the expanded clone differentiate into effector and memory cells; the majority die by apoptosis


Naïve T cells differentiate into functional effector cells responses

Effector T cells

CD4+ helper

T cells

Show naïve CD8 also?

Cytokine

secretion

+ antigen

Differentiation

+ antigen

APC

Naïve T cell:

Can recognize antigen but incapable of any functions

Cell

killing

CD8+ CTLs


Memory t cells
Memory T cells responses

  • Long-lived, functionally silent

    • More numerous than naïve cells specific for the antigen; respond more rapidly than do naïve cells -- explains why secondary response is “better” than primary response

  • Develop from antigen-stimulated T cells

  • May consist of multiple subsets

    • Some migrate to lymphoid organs (like naïve T cells), and proliferate and differentiate rapidly in response to antigen challenge (repeat infection)

    • Others migrate to peripheral sites of infection, and rapidly perform effector functions upon encountering the antigen


The life history of T lymphocytes responses

Precursors mature in the thymus

Naïve CD4+ and CD8+ T cells enter the circulation

Naïve T cells circulate through lymph nodes

and find antigens

Clonal expansion;

differentiation into effector and memory cells

Effector T cells migrate to sites of infection

Eradication of infection


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