T Cell–Mediated Immunity

Activation of T Lymphocytes

By: Noor Abdulrahman

Learning objects

• What signals are needed to activate T lymphocytes, and what cellular receptors are used to sense and

respond to these signals?

• How do a few naive T cells become many effector T cells with diverse functions to eliminate various

microbes?

• What molecules are produced by T lymphocytes that mediate their communications with other cells,

such as macrophages, B lymphocytes, and other leukocytes?

 Contents
• T cell activation and T cell function
• PHASES OF T CELL RESPONSES
• ANTIGEN RECOGNITION AND COSTIMULATION
• Role of Costimulation in T Cell Activation
.
• Stimuli for Activation of CD8+ T Cells
• Development of Memory T Lymphocytes
• BIOCHEMICAL PATHWAYS OF T CELL ACTIVATION
• FUNCTIONAL RESPONSES OF T LYMPHOCYTES TO ANTIGEN AND COSTIMULATION
• Clonal Expansion
• Differentiation of Naive T Cells into Effector Cells
• Development of Memory T Lymphocytes
• MIGRATION OF T LYMPHOCYTES IN CELL-MEDIATED IMMUNE REACTIONS
• DECLINE OF THE IMMUNE RESPONSE
• summary
T cell activation and T cell function

The antigen peptide fragment binds to MHC in APC, then is expressed on the APC membrane.

TCR on T cell binds this complex, activating the T cell

• Helper T cells are activated upon binding to MHC class II –antigen complex presented by APC.

• Cytotoxic T cells are activated upon binding to MHC class I –antigen complex presented by virus-

infected cells or cancer cells.

PHASES OF T CELL RESPONSES

 Naive T cells detect antigens in secondary lymphoid organs, differentiating into effector and memory

cells.

 IL-2, produced by activated T cells, drives rapid proliferation of antigen-specific lymphocytes, known

to as clonal expansion.
  Effector T cells exit lymphoid organs, migrate to infection sites, and eliminate microbes.

Some stay in lymph nodes, signaling B cells to boost antibody responses against the

.
microbes.

Proliferated T cell progeny can become long-lived memory T cells, circulating or residing

in tissues for years. They swiftly respond to subsequent exposure to the same microbe.
ANTIGEN RECOGNITION AND COSTIMULATION

The initiation of T cell responses requires multiple receptors on the T cells recognizing their

specific ligands on APCs.

The TCR for antigen and the CD4 or CD8 coreceptor together recognize complexes of peptide

antigens and MHC molecules on APCs, and this recognition provides the initiating, or first, signal

for T cell activation.

The second signal is thought to provided by the binding of a separate surface protein molecule on

TH cell (CD28) with a protein molecule on APC (B7). Binding between CD28 and B7 delivers the

second signal to TH cell.

Role of Costimulation in T Cell Activation

 The full activation of T cells depends on the recognition of costimulators on APCs in addition to

antige.
.

 The best-defined costimulators for T cells are B7-1 (CD80) and B7-2 (CD86), expressed on APCs.

They interact with CD28, expressed on most T cells.

 A protein called ICOS (inducible costimulator), on T cells, plays an important role in the

development and function of follicular helper T cells.

 CD40 ligand (CD40L, or CD154) on activated T cells and CD40 on APCs. activates the APCs to

express more B7 costimulators and to secrete cytokines (e.g., IL-12) that enhance T cell

differentiation. also enhances activation of B cells and macrophages.

Coinhibitors or Inhibitory receptors are critical for limiting and terminating immune responses.
Two important inhibitory receptors that terminate the responses of cells —CTLA-4 and PD-1.
suppressive function of regulatory T cells.
CTLA-4, like CD28, recognizes B7-1 and B7-2 on APCs, and PD-1 recognizes two different but
structurally related ligands, PD-L1 and PD-L2.
Stimuli for Activation of CD8+ T Cells

Binding of TC cells to MHC class I –viral Ag complex on the cell membrane of the APC

initiates the TC activation.

The activation of CD8+ T cells is stimulated by recognition of class I MHC–associated peptides

and requires costimulation and helper T cells .

BIOCHEMICAL PATHWAYS OF T CELL ACTIVATION

 Upon antigen and costimulator recognition, T cells activate protein expression, triggering proliferation,

differentiation, and effector functions. This initiates diverse biochemical pathways, essential for potent T

cell responses.
FUNCTIONAL RESPONSES OF T LYMPHOCYTES TO ANTIGEN AND COSTIMULATION

 In response to antigen and costimulators, T lymphocytes, especially CD4+ T cells, rapidly secrete the

cytokine IL-2, which is produced within 1 to 2 hours after activation.

 The principal functions of IL-2 are to stimulate the survival and proliferation of T cells

IL-2 was originally called T cell growth factor

Clonal Expansion
Clonal Expansion

 T lymphocytes activated by antigen and costimulation begin to proliferate within 1 or 2 days,

resulting in expansion of antigen-specific clones.

 Differences between CD8+ CTLs and CD4+ effector T cells stem from their distinct functions.

CD8+ CTLs kill infected and tumor cells directly, often requiring many cells for significant

impact. In contrast, CD4+ effector T cells secrete cytokines to activate numerous other effector

cells, potentially achieving substantial effects with fewer cells.

Differentiation of Naive T Cells into Effector Cells

This process of differentiation is the result of changes in gene expression, such as the activation of

genes encoding cytokines .

Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines, which

is very crucial as they secrete distinct cytokines that further mediate specific functions. The subsets

of T cells are distinguished by their cytokine differentiation.

Development of Memory T Lymphocytes

A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells. IL-7 and

IL-15, which are produced by stromal cells in tissues, may serve to keep memory cells alive.

Memory T cells can be found in lymphoid organs, in various peripheral tissues, especially mucosa

and skin, and in the circulation.

MIGRATION OF T LYMPHOCYTES IN CELL-MEDIATED IMMUNE REACTIONS

 Activated naive T cells transform into effector cells and return to infection sites to eliminate

microbes.

 Migration of T cells, naive or effector, is governed by three protein families: selectins, integrins, and

chemokines, which regulate leukocyte migration.

 Naive T cells migrate into lymph nodes via specialized blood vessels called high endothelial venules

(HEVs), facilitated by the expression of adhesion molecule L-selectin (CD62L) and chemokine

receptor CCR7.
The phospholipid sphingosine 1-phosphate (S1P) plays a key role in the egress of T cells from lymph

nodes.

Activated T lymphocytes, including the majority of effector cells, home to sites of infection in

peripheral tissues, and this migration is mediated by E-selectin and P-selectin, integrins, and

chemokines secreted at inflammatory sites.

DECLINE OF THE IMMUNE RESPONSE

After the peak expansion of antigen-specific lymphocytes during an immune response, it's expected that
the system returns to homeostasis, preparing for the next pathogen encounter.

Once an infection is cleared and the stimuli for lymphocyte activation disappear, many of the cells that
.
had proliferated in response to antigen are deprived of these survival signals.

T cell survival and proliferation depend on antigen, CD28 signals, and IL-2 cytokines.
SUMMARY
• The responses of T lymphocytes consist of sequential phases: recognition of cell-associated microbes
by naive T cells, expansion of the antigen-specific clones by proliferation, and differentiation of some
of the progeny into effector cells and memory cells.
• T cells proliferate following activation by antigen and costimulators, resulting in expansion of the
antigen-specific clones. The survival and proliferation of activated T cells are driven by the growth
factor IL-2.
• Naive T cells migrate to peripheral lymphoid organs, mainly lymph nodes draining sites of microbe
entry, whereas many of the effector T cells generated in lymphoid organs are able to migrate to any site
of infection.
• The pathways of migration of naive and effector T cells are controlled by adhesion molecules and
chemokines. The migration of T cells is independent of antigen, but cells that recognize microbial
antigens in tissues are retained at these sites
Thank
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