A BUL A BBAS

S ECTION 12

ACTIVATION OF T-CELLS

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.

C ONTACT I NFORMATION

Abul Abbas, MD (Email)

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

O BJECTIVES
To understand the stimuli that are required for activation of T cells, especially:

To understand the nature and importance of inhibitory receptors of T cells, specifically CTLA-4 and PD-1
To review how knowledge of costimulators and inhibitory receptors has been used to develop new therapies for immunological and other diseases
To understand the functional responses of T cells (proliferation, and differentiation into effector and memory cells) and why each of these responses is necessary for optimal defense against infectious agents.
To briefly review the biochemical mechanisms of signal transduction in lymphocytes, specifically the roles
of kinases and transcription factors activated by TCR
signaling.

1. the importance of antigen recognition for initiat-

ing all responses

67

A CTIVATION OF T C ELLS
K EY WORDS :

ANTIGEN
COSTIMULATION
INHIBITORY RECEPTORS
CYTOKINES
PROLIFERATION; CLONAL EXPANSION
DIFFERENTIATION
NAVE LYMPHOCYTES
EFFECTOR LYMPHOCYTES
MEMORY LYMPHOCYTES

M AIN IDEAS :
The activation of nave 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 signals, promote adhesion with APCs, and control the
migration of T cells to the correct locations.
Nave 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 ensures that T cells respond best to microbial antigens

A BUL A BBAS
and not to harmless substances. The most important
costimulatory pathway for initiating responses of T
cells consists of B7 molecules on APCs and their receptor CD28 on T cells.
Some members of the CD28 family of proteins function to suppress and terminate immune responses.
Blocking these molecules removes the brakes on lymphocyte activation and enhances immune responses,
e.g. against tumors.
Cytokines promote T cell proliferation and differentiation, 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 populations of T cells.
F UNCTIONS OF T CELLS :
- defense against intracellular microbes
- activation of other cells (phagocytes, B lymphocytes)
P HASES OF T CELL RESPONSES
T lymphocytes respond to antigens in two phases:
1. Initiation of response: in peripheral lymphoid organs

68

A CTIVATION OF T C ELLS
- recognition of antigens (MHC - associated peptides) + costimulators
- secretion of cytokines, particularly IL-2 early
- proliferation (clonal expansion): increased number of antigen-specific lymphocytes (leading to increased size of that clone), needed to keep pace
with proliferating microbes
- differentiation into effector and memory cells: conversion of nave lymphocytes (capable only of antigen 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
S TIMULI FOR T CELL ACTIVATION
The signals for T cell activation fall into three broad
groups antigen recognition, costimulation, and cytokines. Each type of signal plays a key role in the activation of T cells.
Antigen recognition:

A BUL A BBAS
- TCR recognizes MHC-peptide complex
- at the same time, CD4 or CD8 (co-receptors) recognize class II or class I MHC, respectively, and thus determine 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 respond, and the system will be at rest before exposure 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 antigens
- 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 responses

- required to start the process of lymphocyte activation

69

A CTIVATION OF T C ELLS
- blocking B7 costimulators suppresses immune responses (in inflammatory diseases, graft rejection)
and blocking the inhibitory receptors enhances immune responses (in cancer and some chronic infections)
Cytokines:
- secreted mediators of immunity and inflammation
- involved in early proliferation (clonal expansion) of T
cells (IL-2), differentiation of nave T cells into effector cells (IL-12, others), and effector functions of
CD4+ T cells (IFN-, IL-4, IL-5, IL-17)
- TH1, TH2 and TH17 subsets of effector CD4+ T cells: secrete 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).

A BUL A BBAS
enough pool of antigen-specific lymphocytes is available to combat infections.
Differentiation: converts antigen-recognizing nave T
cells to effector cells capable of eliminating microbes;
also driven by cytokines (various), costimulation.
S IGNAL 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 proteins, survival proteins, etc).
Engagement of antigen receptors and co-receptors by
peptide-MHC complexes initiates signals by recruiting
adaptor proteins and kinases; multiple signaling intermediates are activated, leading to the generation and activation of transcription factors (NFAT, NF-B, AP-1).
Costimulators enhance signaling by TCRs, and may trigger additional signaling pathways that cooperate with
TCR-induced signals.

F UNCTIONAL RESPONSES OF T CELLS

Proliferation (clonal expansion): driven by costimulation and cytokines (mainly IL-2); ensures that a large
70