Immune System: T-cells and the Immune Response

Explain what is meant by MHC polymorphism, and the consequences for immune responses.

MHC Class I and II are highly polymorphic, thus many different alleles are present in the population which ensures that different individuals are able to present and respond to different microbial peptides. Most of us are heterozygous in our *3* MHC I genes and due to *co-dominant expression* of both parental alleles (it's as if we have 6 genes total). This increases the number of different MHC molecules that can present peptides to T cells. DISADVANTAGE: This is why it's so tough to match donor & recipient for transplants. ADVANTAGE = HUGE! Good example is HIV. Unfortunate people who are heterozygous develop AIDS much more quickly (see image).

(from email) What are the general roles in the immune response of the following types of T cells: TH1, TH2, and Treg cells?

CD4 T cells, when activated, can differentiate into distinct subtypes (sub-lineages). Two major subtypes of CD4 T cells are the *TH1* and *TH2* cells. They serve to direct the cellular (cytotoxic) versus humoral (antibody) immune responses, respectively. Other CD4 subsets exist and are an area of intensive research. *T regulatory cells (Treg)*: • CD4+ CD25+, MHC class II-restricted • regulate immune responses - often inhibitory & prevent autoimmunity

Explain the structural differences between MHC Class I and MHC Class II (Major Histocompatibility Complex).

NOTE: Both types have peptide-binding clefts and are presented on the cell surface. See image for differences.

Explain the characteristics of active immunization and how they differ from passive immunization.

*Active immunity* is acquired when one's immune system responds to an antigen and launches an immune response; after this point you have memory of that antigen & can launch a much quicker response if exposed again. • Natural: from illness/infection • Artificial: from vaccination *Passive immunity* is conferred when specific pre-formed components (antibodies/serum) are transferred from an immunized individual to a non-immunized individual. Usually *obtained from humans or animals* that have been deliberately immunized or have naturally recovered from an active infection (Ex. Ebola). Confers almost *immediate protection*. • Natural: through the placenta or breastmilk • Artificial: injection of antibodies from a donor (or many donors). Usually required for: a. Immunocompromised patients b. People exposed to deadly toxins (Ex. snake bite) c. Rapidly-progressing infections (Ex. rabies)

Describe the effector functions of Cytotoxic, Helper, and Regulatory T cells.

*Cytotoxic T Cells (CD8+)* • Reacts w/ antigenic peptides presented on MHC I (thus from inside the cell) • When costimulated by T helper cells, they become cytotoxic & kill infected cells (virus-infected, tumor) • Peptides derived from endogenous sources *Helper T Cells (CD4+)* • Reacts w/ antigenic peptides presented on MHC II of APC (thus from outside the cell, brought in via endocytosis) • Helps Cytotoxic T cells become cytotoxic (TH1 subset) -OR- helps B cells make antibodies through cytokines & cell-cell interactions (TH2 subset) • Helps APCs become active (cytokines) • Peptides derived from exogenous sources *Regulatory T Cells* • CD4+, CD25+, MHC Class II restricted • Regulate the immune response: mostly inhibitory, prevents autoimmunity

Describe how MHC Class I and Class II peptides are generated.

*MHC Class I peptides* Protein from inside the cell (such as viruses) are marked as foreign then broken down by proteasome. The fragments are taken to the ER where they bind w/ *MHC I*. From there they move through the Golgi to the surface of the cell to present to *CD8 T cells*. NOTE: can occur in virtually any cell of the body. *MHC Class II peptides* Extracellular protein brought in via endocytosis. The material merges w/ a lysosome (end-lysosome) which breaks down the polypeptides. The vesicle then merges w/ another vesicle containing *MHC II*. If the protein product binds, then *MHC II* will go to the surface of the cell and display the polypeptide to *CD4 cells*.

Polymorphism

A high frequency (>1%) of alternate alleles (variants) of a given gene in a population (heterozygous at a given gene/locus).

Antigen presenting cells (APCs)

Dendritic cells, Macrophages, B lymphocytes (and others) that *activate T cells*. Antigen (peptide+MHC) alone will NOT activate a naïve T cell. *Co-stimulation from the APC is essential*. In this essential step in CD4 and CD8 T cell activation, they ingest, process, and "present" protein antigens in the form of peptides recognizable by T lymphocytes (bound to MHC). APCs then express co-stimulatory molecules (such as B7) that are necessary to activate T cells.

When/where do T cells acquire CD4 and CD8 cell surface markers?

During development in the thymus.

Describe the cell types and steps involved in T cell activation.

Unlike B cells, T cells react w/ *peptides* derived from the breakdown of antigenic proteins - *T CELLS DO NOT REACT WITH FREE ANTIGEN* (Ex: whole virus - B cell can recognize it; T cell needs it to be broken down) • Phagocytic cells, like dendritic cells (DCs), macrophages, and B cells, ingest foreign antigens and present them bound to an MHC molecule (Major Histocompatibility complex) on their surface. • The APC (antigen presenting cell) takes the peptide particle on MHC to the secondary lymph tissues to present to T cells. • The T cell binds to the peptide on MHC w/ its T cell receptor (TCR) and co-stimulates w/ either CD4 (if peptide came from outside the cell) or CD8 (if peptide came from inside the cell, ex virus), activating the T cell.

Explain the basic, unique genetic features of MHC molecules.

• The genes that encode for MHC I and II are highly polymorphic • High frequency of alternate alleles for a given gene • A single cell can display up to 6 different types of MHC I, all of which are capable of recognizing different protein segments • A single APC can display at minimum 3 different MHC II, but could be many more due to polymorphism • This allows MHC to recognize and bind to a much broader range of polypeptide groups

Describe some of the undesirable immune reactions.

• The immune response can be *hyperactive*; in the case of allergies, the immune response can be overwhelming and it can occur more and more frequently. The reaction is to innocuous substances. • *Autoimmunity*: adaptive immune response against "self" antigens. There is disregulation and breakdown in the T cell and antibody response. • Transplant rejection: due to the different MHC I Class receptors present in every person (multiple possible combinations of genetic material to form them), it is difficult to match people exactly so that when the organ is transplanted, it recognized as foreign and rejected. *Immunosuppression* is needed to prolong the survival of the graft.