4.5 - Cell-Mediated Immune Response

Cell-mediated immunity

Driven by T cells; defends against intracellular pathogens by directly attacking infected cells

Humoral vs. cell-mediated immunity (targets)

Humoral (B cells and antibodies) targets extracellular pathogens by circulating in body fluids; cell-mediated (T cells) targets intracellular pathogens by directly attacking infected cells

Thymocytes

Immature T cells that develop into fully functional T cells through positive and negative selection

T cell tolerance

The process of eliminating T cells that might attack the cells of one's own body

Positive selection

In the thymic cortex, thymocytes bind MHC molecules on thymic epithelia, and those that can bind self-MHC (class I or II) are selected; those unable to bind are eliminated; results in MHC restriction

Survival of thymocytes

Only about two percent of thymocytes that enter the thymus leave as mature, functional T cells

MHC restriction

Result of recognizing self-MHC in positive selection; survivors are restricted to recognizing antigen presented on self-MHC

Negative selection

Self-antigens are presented to immature T cells by peptide-presenting cells of the thymus; T cells that bind self-antigens are killed by apoptosis

T cells remaining after selection

Only those that can bind the body's MHC molecules with foreign antigens presented on their binding sites, preventing attack on the body's own tissues

Breaking of T cell tolerance

Can occur through the development of an autoimmune response

Selection of T cells (Figure 4.29)

Positive selection: T cells must recognize self-MHC or are eliminated by apoptosis; negative selection: T cells must not recognize self-antigens, or self-reactive cells are eliminated by apoptosis; failure to bind self-antigen tightly allows survival, maturation, and release from the thymus

Inactive T cell receptors

Bind class I or class II MHC proteins, but not both; also have binding sites for a specific antigen, with binding occurring when an antigen matches a specific receptor

CD markers

"Cluster of differentiation" markers in T cell membranes; the molecular basis of antigen recognition; more than 350 different types

CD8 marker

Responds to antigens on class I MHC proteins; found on cytotoxic T cells, regulatory T cells, and memory T cells

CD4 marker

Responds to antigens on class II MHC proteins; found on helper T cells and memory TH cells

CD4 and CD8 expression

Mature T cells express either CD4 or CD8, but not both

Function of CD4/CD8 as adhesion molecules

Keep the T cell in close contact with the antigen-presenting cell by binding the MHC molecule (at a different part than the antigen); T cell and target are held together by CD4/CD8 attaching to MHC and by the T cell receptor binding antigen

Activation by class I MHC proteins

Antigen on class I MHC indicates an infected or abnormal cell; activates CD8 T cells, which differentiate into cytotoxic T cells, memory Tc cells, and regulatory T cells

Activation by class II MHC proteins

Antigen on class II MHC indicates presence of pathogens, toxins, or foreign proteins; activates CD4 T cells, which differentiate into helper T cells and memory TH cells

Clonal expansion (T cells)

Rapid proliferation by mitosis of a mature T cell activated by recognizing processed foreign antigen with a self-MHC molecule; necessary to make the immune response strong enough to control a pathogen

T cell specificity

Based on the amino acid sequence and 3-D shape of the antigen-binding site formed by the variable regions of the two chains of the T cell receptor

Clonal selection (T cells)

Process of antigen binding only to those T cells that have receptors specific to that antigen

Clone

Group of lymphocytes that share the same antigen receptor; progeny of an activated T cell have identical DNA and T cell receptors

Size of each clone before activation

Each clone is present in the body in low numbers; otherwise there would be no room for lymphocytes with so many specificities

Polyclonal response

Stimulation of multiple types of T cell clones; typical because most antigens have multiple antigenic determinants

Costimulation

After binding the target cell, a T cell must bind at a second site to confirm the first signal before it becomes active; then undergoes activation and division, producing more T cells of the same type and memory T cells

Antigen recognition by CD4/CD8

CD4 and CD8 markers first bind antigen through the receptor complex and prepare the cell for activation

CD8 T cell activation (Figure 4.31)

1) Antigen recognition: CD8 T cell encounters antigen bound to class I MHC; 2) costimulation leads to activation and division, producing active Tc cells and memory Tc cells; 3) active Tc cells destroy the antigen-bearing cell

Functional roles of CD4 vs. CD8 T cells

CD4-bearing T cells are associated with helper functions; CD8-bearing T cells are associated with cytotoxicity

CD8 cell types

One type responds quickly, producing cytotoxic T cells; another responds more slowly, producing regulatory T cells

Cytotoxic T cells (Tc)

Kill target cells by inducing apoptosis using a mechanism similar to NK cells (perforins, cytokines, granzymes)

Perforins (Tc cells)

Insert into the target cell membrane, forming pores like those produced in complement activation

Cytokines (Tc cell killing)

Chemical messengers that activate genes in the target cell to trigger apoptosis

Granzymes (Tc cells)

Enter the target cell via the pores and degrade the cellular contents

Actions of cytotoxic T cells (Figure 4.33)

1) Binds tightly to the foreign target cell; 2) releases perforin and granzymes from granules by exocytosis; 3) perforin inserts into the target membrane forming pores; 4) granzymes enter via pores and degrade cellular contents; 5) Tc cell detaches and searches for another target

Effectiveness of Tc cells

Killing a virally infected cell before the virus completes replication yields no infectious particles; more Tc cells overwhelm the virus; each Tc cell can kill more than one target cell; some speculate antiviral immunity was the main reason adaptive immunity evolved

Regulatory (suppressor) T cells

Form from CD8 T cells; suppress other T cell immune responses and antibody activation; prevent uncontrolled clonal expansion that could lead to autoimmune diseases and other medical issues

Helper T cells (TH)

Bear the CD4 molecule and respond to antigens on class II MHC; secrete cytokines that enhance other immune responses; act like an "on-switch" for both humoral and cellular adaptive immunity

Th1 helper cells

Effector helper T cells that secrete cytokines to activate cytotoxic T cells (also regulate macrophage and T cell activity)

Th2 helper cells

Effector helper T cells that secrete cytokines to cause B cells to differentiate into antibody-producing plasma cells

Memory helper T cells (TH)

Created to continue immune surveillance and can activate if a pathogen is detected later

HIV and helper T cells

HIV infection targets helper T cells; as the population decreases, patients become immunocompromised and at risk for life-threatening opportunistic infections

Memory T cells

Memory TH and memory Tc cells; generated with effector T cells in a primary response; long-lived (can persist for a lifetime); primed to act rapidly on re-exposure

Effector T cells

Generated during a primary adaptive response; secondary response generates large numbers so fast that the pathogen is often overwhelmed before it causes symptoms (immunity to a disease)

Adaptive immune system actions (Figure 4.34)

Antigen is engulfed by a macrophage, which presents it to a helper T cell; helper T cell divides into effector helper T cells (activate naive B cells and naive cytotoxic T cells) and memory helper T cells; B cells yield plasma cells and memory B cells; cytotoxic T cells yield effector and memory cytotoxic T cells

Targets of antibodies vs. effector cytotoxic T cells

Antibodies target pathogens or toxins outside of cells; effector cytotoxic T cells target cells infected with intracellular pathogens, cancer cells, and cells of organ transplants

Cytotoxic T cells (CD8) function summary

Fight intracellular infections (virus-infected cells) and cancer cells by killing cells with class I MHC presenting a foreign antigen; secrete perforins and granzymes

Helper T cells (CD4) function summary

Regulate the adaptive immune system; Th1 regulate activity of macrophages and T cells; Th2 regulate B cells by triggering differentiation into plasma cells

Regulatory T cell function summary

Suppress the cellular immune response to maintain tolerance

B cells (summary)

Lymphocytes that are APCs and can expand and differentiate into plasma cells

Plasma cells (summary)

Secrete antibodies to specific antigens

Memory cells (T and B) summary

Population with extended lifespan ready to expand if the antigen returns in the future

Tissue typing

Determination of MHC molecules in the tissue to be transplanted to better match donor to recipient

Transplant rejection

Recipient's immune system identifies the transplanted tissue as foreign and attacks and destroys the graft; mediated by the recipient's T cells and antibodies recognizing mismatched MHC molecules on donor tissue

Major cause of transplant rejection

MHC molecules on body tissues; makes transplantation more complicated than blood transfusion

Histocompatibility

Property of having the same, or mostly the same, genes coding for MHC molecules, reducing the risk of rejection in tissue and organ transplants

MHC polygeny

Multiple MHC proteins on each cell

MHC polymorphism

Multiple alleles for each person's MHC molecules; gives population diversity in immune responses but makes it more difficult to find a donor-recipient MHC match

Why MHC matching is harder than blood matching

MHC polygeny and MHC polymorphism

Mismatched MHC and rejection

Recipient often mounts a cytotoxic T cell response to the donor organ and rejects it; massive T lymphocyte infiltration on biopsy in the first weeks signals likely failure; a classical, specific primary T cell response

Graft-versus-host disease

Can occur with bone marrow transplants: donor lymphocytes attack the recipient's other tissues because the recipient's immune response was destroyed before transplant; symptoms usually include a rash and damage to the liver and mucosa; moderated by first removing mature T cells from the donor marrow

Immunosuppressive drugs

Diminish the strength of the immune response to prevent attack on a transplant; target specific immune cells such as T cells, inhibit antibody production, or block signaling pathways that activate the immune response

MHC matching for transplants

Six MHC molecules show the most polymorphisms; success usually requires a match of at least 3-4, with more matches giving greater success; family members are more likely to match; unrelated donors are found only through a worldwide database, which often lacks enough donors