SECTION 12

ACTIVATION OF T-CELLS

CONTACT INFORMATION

Abul Abbas, MD (Email)

READING

Basic Immunology: Functions and Disorders of the Immune System. Abbas, Abul K., and An-drew H. Lichtman. -- Chapter 5

OBJECTIVES

• To understand the stimuli that are required for activa-tion of T cells, especially:

1. the importance of antigen recognition for initiat-ing all responses

2. the role of costimulation in regulating responses to microbes, particularly costimulation by the B7:CD28 pathway, and

3. the functions of cytokines, specifically IL-2, in stimulating T cell proliferation.

• To understand the nature and importance of inhibi-tory receptors of T cells, specifically CTLA-4 and PD-1

• To review how knowledge of costimulators and inhibi-tory receptors has been used to develop new thera-pies for immunological and other diseases

• To understand the functional responses of T cells (pro-liferation, and differentiation into effector and mem-ory cells) and why each of these responses is neces-sary for optimal defense against infectious agents.

• To briefly review the biochemical mechanisms of sig-nal transduction in lymphocytes, specifically the roles of kinases and transcription factors activated by TCR signaling.

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KEY WORDS:

• ANTIGEN

• COSTIMULATION

• INHIBITORY RECEPTORS

• CYTOKINES

• PROLIFERATION; CLONAL EXPANSION

• DIFFERENTIATION

• NAÏVE LYMPHOCYTES

• EFFECTOR LYMPHOCYTES

• MEMORY LYMPHOCYTES

MAIN IDEAS:

• The activation of naïve T lymphocytes is initiated by recognition of antigen presented by dendritic cells in lymphoid organs. Antigen provides specificity, and other molecules on the T cells trigger biochemical sig-nals, promote adhesion with APCs, and control the migration of T cells to the “correct” locations.

• Naïve T lymphocytes also require signals provided by costimulators, molecules that are expressed on APCs in response to microbes and provide stimuli for T cell activation in addition to antigen. Costimulation en-sures that T cells respond best to microbial antigens

and not to harmless substances. The most important costimulatory pathway for initiating responses of T cells consists of B7 molecules on APCs and their re-ceptor CD28 on T cells.

• Some members of the CD28 family of proteins func-tion to suppress and terminate immune responses. Blocking these molecules removes the brakes on lym-phocyte activation and enhances immune responses, e.g. against tumors.

• Cytokines promote T cell proliferation and differentia-tion, and are involved in various effector functions of the T cells. IL-2 is the most important growth factor, required for expansion of antigen-stimulated popula-tions of T cells.

FUNCTIONS OF T CELLS:

- defense against intracellular microbes

- activation of other cells (phagocytes, B lymphocytes)

PHASES OF T CELL RESPONSES

T lymphocytes respond to antigens in two phases:

1. Initiation of response: in peripheral lym-phoid organs

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- recognition of antigens (MHC - associated pep-tides) + costimulators

- secretion of cytokines, particularly IL-2 early

- proliferation (clonal expansion): increased num-ber of antigen-specific lymphocytes (leading to in-creased size of that clone), needed to keep pace with proliferating microbes

- differentiation into effector and memory cells: con-version of naïve lymphocytes (capable only of anti-gen recognition) into effector cells (capable of eliminating microbes) and memory cells (able to respond more rapidly upon antigen encounter)

2. Effector phase of response: in lymphoid and non-lymphoid tissues

- elimination of microbes

- help for B cells

STIMULI FOR T CELL ACTIVATION

The signals for T cell activation fall into three broad groups – antigen recognition, costimulation, and cytoki-nes. Each type of signal plays a key role in the activa-tion of T cells.

Antigen recognition:

- required to start the process of lymphocyte activation

- TCR recognizes MHC-peptide complex

- at the same time, CD4 or CD8 (“co-receptors”) recog-nize class II or class I MHC, respectively, and thus de-termine the specificity of CD4+ and CD8+ T cells for class II vs class I - associated peptides

- adhesion molecules (integrins) stabilize contact with APCs

- the need for antigen recognition to initiate all lymphocyte responses ensures that only cells with specific receptors for the antigen will re-spond, and the system will be at rest before ex-posure to antigen

Costimulation:

- signals other than antigen that are generated during innate immune responses to microbes; ensure that T cells respond to microbes and not to harmless anti-gens

- major costimulators for T cells are B7 molecules on APCs (upregulated by microbes), which engage the CD28 receptor on T cells and activate T cells

- CTLA-4 and PD-1, which are homologous to CD28, inhibit lymphocyte activation and limit immune re-sponses

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- blocking B7 costimulators suppresses immune re-sponses (in inflammatory diseases, graft rejection) and blocking the inhibitory receptors enhances im-mune responses (in cancer and some chronic infec-tions)

Cytokines:

- secreted mediators of immunity and inflammation

- involved in early proliferation (clonal expansion) of T cells (IL-2), differentiation of naïve T cells into effec-tor cells (IL-12, others), and effector functions of CD4+ T cells (IFN-γ, IL-4, IL-5, IL-17)

- TH1, TH2 and TH17 subsets of effector CD4+ T cells: se-crete different combinations of cytokines, which are responsible for the distinct functions of the subsets (discussed in detail in a later lecture)

Activation of CD8+ T cells usually requires help from CD4+ T cells; this is why CTL responses are defective in HIV-infected patients (remember that HIV infects only CD4+ cells, which are mainly helper T cells and also some macrophages and dendritic cells).

FUNCTIONAL RESPONSES OF T CELLS

Proliferation (clonal expansion): driven by costimula-tion and cytokines (mainly IL-2); ensures that a large

enough pool of antigen-specific lymphocytes is avail-able to combat infections.

Differentiation: converts antigen-recognizing naïve T cells to effector cells capable of eliminating microbes; also driven by cytokines (various), costimulation.

SIGNAL TRANSDUCTION IN T CELLS

The goal of signal transduction is to link the process of antigen recognition to the activation of selected genes (encoding cytokines, cytokine receptors, cell cycle pro-teins, survival proteins, etc).

Engagement of antigen receptors and co-receptors by peptide-MHC complexes initiates signals by recruiting adaptor proteins and kinases; multiple signaling inter-mediates are activated, leading to the generation and ac-tivation of transcription factors (NFAT, NF-κB, AP-1).

Costimulators enhance signaling by TCRs, and may trig-ger additional signaling pathways that cooperate with TCR-induced signals.

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