Lecture 24: Cellular immunity, MHC and histocompatibility

Learning Objectives

  1. Know what is meant by cellular immunity

  2. Understand the role of the thymus in T cell development and tolerance

  3. The names and functions of the 2 main T lymphocytes subsets

  4. Know what is meant by histocompatibility and the role of MHC

  5. Understand what is meant by MHC restriction and it’s importance to immunity

  6. Be able to describe the T cell receptor and MHC peptide complex

  7. Understand the important differences between MHC class 1 and class 11

  8. Know the roles of the co-receptors CD4 and CD8 in defining the function CTL and HTL functions

  9. Understand why MHC is polymorphic and so important to medicine

Defense Against Pathogens

The body defends against pathogens through:

  • Anatomical and Physiological Barriers:

    • Intact skin.

    • Low stomach pH.

    • Ciliary clearance.

    • Lysozyme in tears and saliva.

  • Innate Immunity:

    • Natural Killer (NK) Cells.

    • Neutrophils.

    • Natural Killer T (NKT) Cells.

    • Eosinophils.

    • Macrophages.

    • Mast Cells.

    • Dendritic Cells.

    • Complement.

    • Mannose-Binding Lectin.

    • Antimicrobial Peptides.

    • LPS Binding Protein.

    • C-Reactive Protein.

  • Adaptive Immunity:

    • Cellular:

      • T cells.

    • Humoral:

      • B cells.

      • Antibodies.

Cellular Immunity Against Viruses

  • Viruses are intracellular pathogens that rely on the host cell's machinery to replicate.

  • Cellular immunity detects "flags" presented on the infected cell surface, which are molecules presenting viral fragments to the immune system.

  • It can also detect abnormal changes in cancer cells.

The Thymus

  • The thymus is the site of T cell development. It is a primary lymphoid organ, largest at birth and shrinks with age. Located above the heart.

  • Haemopoietic lymphoid precursors migrate from the bone marrow to the thymus, where they mature into T lymphocytes.

  • Only a small percentage of T cells survive the thymus and become mature peripheral T cells.

  • The thymus is where T cells learn not to react to self-cells, a process called thymic education. Thymic education is the first step for immune tolerance.

  • Autoimmune disease results from the breaking of tolerance.

The T Lymphocyte

  • Immature thymocytes are CD4+CD8+.

  • Mature T cells differentiate into two main functional types:

    • CD8+ cytotoxic T cells (~20% in blood).

    • CD4+ helper T cells (~80% in blood).

      • Subsets: Treg, Th1, Th2, Th17.

Immune Response to Viral Infection

  • T cells rely on surface molecules to determine if a cell is normal or abnormal and the type of immune response needed. These molecules are highly polymorphic proteins initially identified for controlling tissue transplantation.

  • The gene complex coding for these molecules is called the Major Histocompatibility Complex (MHC).

  • Human MHC proteins are called Human Leukocyte Antigens (HLA).

  • T cells only recognize antigen when presented alongside MHC molecules.

Histocompatibility

  • Two strains of mice (A and B) have different sets of MHC genes.

  • Transplanting skin from one mouse to another results in graft rejection because the recipient's T cells react to the donor's MHC molecules as foreign.

  • The same principle applies to humans.

  • Organ transplantation requires careful matching of MHC genes between donor and recipient, called tissue typing.

MHC Polymorphism

  • Everyone has the same set of MHC genes, but the DNA sequences vary greatly between individuals.

  • Multiple MHC molecules exist (6 main ones), and both maternal and paternal genes are expressed, resulting in 12 separate MHC molecules for every person's cells.

  • MHC polymorphism is extensive; two people (except identical twins) rarely have the same set of MHC genes.

  • The genetic polymorphism leads to amino acid variation in HLA molecules around the peptide-binding cleft. This variation makes it difficult to find suitable donors for transplants.

MHC Restriction

  • Viral immunity requires the immune system to recognize two antigenic components:

    • SELF: Antigen(s) encoded by MHC.

    • NON-SELF: Antigen(s) encoded by the virus.

Molecules Involved in MHC Restriction

  • The T cell Receptor (TCR) is a membrane-bound Ig-like molecule on T lymphocytes. Its genes undergo gene rearrangement.

  • Highly polymorphic HLA molecules are expressed on most cells and present peptide antigens to T cells.

  • The antigen-binding site of a TCR is formed similarly to an antibody but is tightly restricted to MHC molecules. This restriction occurs during thymic education.

MHC Class I

  • Viral peptide is synthesized inside the cell.

  • Shows polymorphism.

MHC Class II

  • Peptide is obtained from outside the cell.

MHC Class I & II

  • MHC class I and class II serve different roles.

  • MHC class I + Epstein Bar Virus peptide.

  • MHC class II + influenza peptide.

CD4 and CD8 as T Cell Co-receptors

  • CD4 and CD8 are accessory molecules on T cells that physically associate with the TCR/MHC/peptide complex.

  • CD8 = Cytotoxic T cells recognize peptides in MHC class I.

  • CD4 = Helper T cells recognize peptides in MHC class II.

  • CD4 and CD8 have intracellular tyrosine kinases associated with their cytoplasmic tails that signal through phosphorylation.

  • They are crucial to the first activation step of the cascade that leads to your immune response and steering it in the right direction.

CD4+ Helper T Cell Function

  • CD4+ helper T cells recognize peptides presented by MHC class II on antigen-presenting cells (APCs). They proliferate into a helper cell phenotype that directs the immune response.

    • Examples: tells B cells to make antibodies, directs CTL to kill cancer cells, or downregulates the immune response.

  • AIDS is caused by the loss of CD4 helper T cells that are killed by the HIV virus.

  • Treg, Th1, Th2, Th17 are 4 important T helper subsets.

CD8+ Cytotoxic (CTL) Function

  • CD8+ CTL recognizes peptides presented by MHC Class I. Produces granzyme and perforins that punch holes in the target cell membrane and destroy cell viability. Also kills by direct apoptosis.

Roles of MHC Class I, MHC Class II, CD4, and CD8 T cells

Peptide Source

Pathogen

Responding T cells

Effector Function

MHC Class

Class I

Intracellular

Viruses

CD8

Cytotoxic

MHC Class I

Class II

Extracellular

Bacteria

CD4

Help

MHC Class II

Why MHC Evolved Such Polymorphism

  1. To be able to bind as many peptides as possible

  2. To diversify a population’s response and survival to emerging pathogens.

Consequences of MHC Polymorphism

  1. Tissue transplantation is difficult except between identical twins. Donor MHC is seen as “non-self” and is “rejected” by the recipient’s T cells. Requires careful tissue typing (HLA matching) for donor selection.

  2. MHC polymorphisms are strongly linked to many autoimmune diseases. Certain MHC haplotypes are over-represented in people with diabetes, Multiple Sclerosis, Ankylosing Spondylitis, Rheumatoid Arthritis.

MHC Linked Diseases

  • Addison’s disease

  • Juvenile Type I Diabetes

  • Rheumatoid Arthritis

  • Multiple Sclerosis

  • Ankylosing Spondylitis

NB You don’t have to remember these associations – given as examples of major autoimmune diseases

Key Learning Points

  1. Cellular immunity is regulated by the Major Histocompatibility Complex. A set of highly polymorphic genes coding for a group of membrane molecules called HLA in humans.

  2. The thymus is the organ where T cells develop and learn what self MHC looks like.

  3. The T cell Receptor (TcR) is an Ig-like membrane molecule. Its gene locus is segmented and undergoes rearrangement just like Ig. It recognises small peptides bound inside MHC molecules.

  4. Tissue rejection results from a difference in the polymorphic MHC proteins between donor and recipient

  5. MHC molecules come in two types - class I and class II. Both have a peptide binding grove that holds a foreign peptide. The amino acid polymorphism in MHC is located around the peptide grove.

  6. T cells are divided into two functionally different populations marked by the CD4 and CD8 antigens.

  7. CD4 and CD8 are accessory molecules associated with the T cell Receptor responsible for intracellular signalling through associated tyrosine kinases.

  8. CD8+ T cells are cytotoxic and recognise viral antigens presented by MHC class I.

  9. CD4+ T cells are helper T cells that recognise bacterial antigens presented by MHC class II.

  10. MHC polymorphism is why tissue transplantation is so difficult.

  11. MHC polymorphisms are strongly linked to many autoimmune diseases. It is the only part of your genome that is so polymorphic.