MHC and T Cell Activation

MHC and Antigen Presentation & T Cell Activation

• MHC proteins bind to peptide fragments and display them on the cell surface, acting like a barcode.
• T cells use MHC proteins to identify abnormal proteins on cells, potentially due to viral/bacterial invasion, cancer, or foreign cells.
• MHC, a major histocompatibility complex, is a tightly linked cluster of genes present in vertebrates.
• These genes regulate intercellular recognition and self/non-self discrimination.
• MHC is located on chromosome 6 in humans and chromosome 17 in mice.

MHC Classes

• MHC genes are organized into three classes.
• Class I MHC genes: Glycoproteins expressed on all nucleated cells. Their main function is to present peptide antigens to cytotoxic T cells (Tc cells).
• Class II MHC genes: Glycoproteins expressed on antigen-presenting cells (APCs) like macrophages, B cells, and dendritic cells. Their main function is to present processed antigen peptides to helper T cells (TH cells).
• Class III MHC genes: Not membrane proteins. They aren't directly involved in antigen presentation but play roles in the immune response, including complement components and heat shock proteins.

MHC Class I Molecules

• Molecular weight: 45 kD.
• Found on almost all nucleated cells (except red blood cells).
• Bind to portions of antigens (peptide fragments).
• Presents the fragments on the cell surface.
• Cytotoxic T cells recognize and initiate specific immune defenses against cells with these displayed antigens.

MHC Class I Protein Structure

• Membrane-spanning molecule, approximately 350 amino acids long.
• Transmembrane and cytoplasmic portions comprise 75 amino acids.
• Remaining 270 amino acids are divided into three globular domains (α1, α2, and α3).
• A second portion called β2-microglobulin is associated with the a3 domain, crucial for MHC stability.
• β2-microglobulin is a highly conserved protein encoded on different chromosomes.
• α1 and α2 domains form an 8-antiparallel β-strand structure connected by two long α-helices creating a peptide-binding cleft.
• The cleft can contain small 8-10 amino acid peptides and present these peptide fragments to T cells.

MHC Class II Molecules

• Composed of two polypeptide chains (alpha and beta).
• About 230 and 240 amino acids long, respectively, and glycosylated, giving molecular masses of approximately 33 kDa and 28 kDa.
• The polypeptide chains fold into two separate domains (a1 and a2 for alpha, and β1 and β2 for beta).
• A region between the α1 and β2 domains is similar to Class I MHC, acting as a peptide-binding cleft for 10–15 amino acid peptides.

MHC II Structure Overview

• MHC II molecules are composed of a polymorphic α-chain and a non-polymorphic β-chain joined non-covalently.
• Both chains are glycosylated.
• The cleft, formed by portions of the α and β polypeptide chains, is a site where antigenic peptides are presented on the cell surface to T cells..

Antigen Processing and Presentation

• Foreign proteins are degraded into small antigenic peptides.
• Peptides combine with MHC I or II molecules.
• This process is called antigen processing and presentation. The route the antigen takes into the cell determines if it is processed and presented with MHC I or MHC II.

Endogenous Pathway

• Endogenous antigens originate within the cell (e.g., viral proteins, proteins from cancerous cells).
• These proteins are degraded into peptides in the endoplasmic reticulum, and the peptides bind to MHC I molecules.
• MHC I-peptide complexes are transported to the cell surface, where they are recognized by cytotoxic T cells (CD8+).

Exogenous Pathway

• Exogenous antigens originate outside the cell (e.g., ingested bacteria).
• These antigens are engulfed by the cell via endocytosis or phagocytosis.
• Inside the cell, the antigens are degraded into peptides within endocytic vesicles.
• Peptides bind to MHC II molecules within the endocytic vesicles.
• MHC II-peptide complexes are transported to the cell surface, where they are recognized by helper T cells (CD4+).

T-Cells

• Develop in the thymus.
• Involved in cell-mediated immunity.
• Feature: T cell receptor (TCR).
• Types include helper, cytotoxic, memory, regulatory, and γδ T cells.
• T cells eliminate pathogens in infected cells and assist B cells in antibody production.
• T cells identify and eliminate cells harboring pathogens.

T Cell Receptor (TCR)

• A protein complex found on T cells.
• Recognizes peptides bound to MHC molecules (not freely circulating peptides).
• TCR is part of the immunoglobulin superfamily.
• The TCR is a heterodimer (either αβ or γδ) – two disulfide-linked polypeptide chains normally consisting of highly variable α and β chains expressed as part of complex with invariant CD3 chain molecules.
• TCR diversity arises from a combinatorial approach of diverse chains.

TCR Diversity

• TCRs are highly variable in individuals.
• Antibody diversity is similar..
• TCR diversity is due to small changes in the charge and shape; random aspects of TCR structure contribute..
• TCR diversity and generation mechanisms are analogous to immunoglobulin genes.

The Challenge T Cells Face

• Require a large number of T cell clones (~10¹³).
• Peptides are ~10 amino acids long.
• Millions of possible peptides with various amino acid combinations.
• Multiple germline segments are combined for TCR diversity. Somatic recombination and selection mechanisms form the basis for massive TCR diversity and avoid self-recognition.

CD4 Co-Receptor

• CD4 is a co-receptor for TCR in helper T cells.
• It binds to MHC class II molecules.
• Its intracellular domain binds to Lck tyrosine kinase.
• CD4 mediates TCR signaling and intracellular cascade events.

CD8 Co-Receptor

• CD8 is a co-receptor for TCR in cytotoxic T cells; it's expressed as a dimer (alpha and beta chains).
• It binds to class I MHC molecules.
• CD8 ensures tight binding and delivers downstream signals through Lck to TCR

B7-CD28 Co-stimulation

• Crucial for T cell activation.
• Requires both antigen recognition and co-stimulation (e.g., B7-1 and B7-2 interacting with CD28).
• Prevents activation by antigens on normal cells.
• Suppresses T cell responses when CTLA4 is activated.

Lymphocytes (T cells and B cells)

• Immature lymphocytes from bone marrow are fundamentally similar.
• T cell maturation takes place in the thymus.
• B cell maturation occurs in the bone marrow.

T-Cell Types

• Helper T cells (CD4+) secrete cytokines to activate B and other immune cells.
• Cytotoxic T cells (CD8+) directly eliminate infected cells.
• Regulatory T cells (Tregs) modulate immune responses.

Key Steps in T-cell Activation

• APC's have to process and present peptides to T cells (either exogenously or endogenously produced).
• T cell binding to APC requires secondary signal of costimulatory molecules.
• Accessory adhesion molecules help stabilize the binding.
• Cytokine signals from cell surfaces are relayed to the cell nucleus for division.

MHC Class III

• Contains components crucial for the formation of complement convertase (e.g., C2, C4, and factor B).
• Includes heat shock proteins and tumor necrosis factors.

Explore the critical role of MHC proteins in antigen presentation and T cell activation. This quiz covers the organization of MHC classes and their function in immune response. Test your understanding of how these proteins help T cells identify abnormal proteins in the body.