Lecture 145: Immunogenetics, Lymphocyte Activation, Immune Regulation Tolerance I

Antigen Recognition by T lymphocytes

TCR specific for one antigen

• TCR: protein dimer with a variable region and constant region
• can only activate T cells capable of binding to particular antigen on surface

What makes B cells different from T cells?

can recognize peptides + polysaccharides

once T cell is stimulate by antigen, no other changes can happen to receptor BUT

• B cells: somatic hypermutation can happen: better binding to antigen through mutations

MHC

also known as HLA

• polymorphic
• different variations

Transplant rejection: difference between MHC genes of donors and recipients

Relationship between Allelic variation and MHC

most humans are heterozygous for MHC genes with various combinations inherited from parents

• this heterozygosity of MHC - allows large variety of peptides to be displayed on TCR
• antigens generated from degradation of self and non self proteins

Difference between MHC molecule vs TCR

MHC molecule: can bind multiple peptides but TCR can only recognize one peptide at a time

roles of MHC and TCR on Antigen processing and presentation

MHC Class I molecule

present peptides from intracellular pathogens on CD8 or cytotoxic cells

• kill virus or tumor infected cells
• Cytotoxic T cells limit the spread of intracellular pathogens by killing the infected cells that display foreign antigens
• proteins degraded in cytosol

MHC Class II

APC present peptide antigens from EC pathogens to CD4 cells (helper cells)

• degraded in lysosomes and vesicles

Main function of MHC II

present peptides on surface of APC (dendritic, macrophages, B cells) to CD4 cells

Mechanism of Helper T cells

defend against extracellular infections by enhancing the phagocytosis of extracellular pathogens by macrophages and
by stimulating B cells to make antibodies

General principle of T cells function

make contact with other cells and induce them to change

Pathway between CD4 cells and macrophage interaction

CD4 + macrophage - cytokine IFN gamma activated - macrophages produce IL12 - promotes more Th1 cells from CD4

• Th1 produce IFN g - promote macrophage phagocytosis

How do peptides move inside cytoplasm of APC?

TAP (transporter associated with antigen processing)

• transports peptides across ER - associate with MHC I - inserted to PM

Autoimmunity

• loss of tolerance
• self reactive CD8 cells respond to self peptides displayed on MHC class I molecules

EX: RA, IBD, Lupus, MG, Graves

Structure of MHC I

membrane glycoproteins found on all nucleated cells which binds antigens and present to CD8

• DIMER: alpha chain noncovalent bonded to beta 2 microglobulin

What mediates binding of MHC I to CD8 and what is the function?

alpha 3 portion of alpha protein

• ensures that MHC I molecules present peptides to only CD8 cells

Structure of MHC II

2 transmembrane proteins: alpha + beta

• form peptide binding dimer at cell surface
• alpha 1 + beta 1 form peptide binding site

What mediates CD4 and MHC II binding site?

beta 2 domain

• makes sure that molecules present peptides only to CD4 helper cells

MHC Class I isotypes

HLA A, B, C, E, G F
6 types

MHC class II isotypes

5 types

• DM
  DO
  DP
  DQ
  DR

Haplotype

particular combination of HLA alleles that an individual inherits

• most families: parental haplotypes intact

What do MHC polymorphisms affect?

binding and presentation of peptide antigens to T cells

Cross Match Test

check if patient and donor serum will match

• no reaction: can give transfusion
• donor cells die: not match

Mixed lymphocyte reaction

in vitro

• measure T cell proliferation (measure DNA syn from Radiolabeled NA) and cytotoxicity

= extent to which T cells respond to HLA expressed on donor cells

Bacterial superantigens

massive but ineffective harmful T cell response

• causes many T cells to divide and differentiate to effector T cells in excessive response - death by apoptosis or exaggerated clonal expansion

Examples of superantigens

Staphylococcal toxic shock syndrome toxin &
streptococcal M protein. Also, the serious form of
COVID-19

What results in sequence variability of variable region of TCR?

gene rearrangements during T cell development

Gene rearrangements of TCR

Both TCR and IG: recombination of V,D,J

Alpha chain: V + J recombination = variable region

Beta chain: D+J joined by recombination + V

NO SOMATIC HYPERMUTATION

What are the initial steps in lymphocyte activation?

TCR (8 polypeptides) binding to antigen - MHC complex and signal transduction

Function of dendritic cells

Dendritic cell binding to T cells process

CD2 + LFA3 allows LFA1 to interact with ICAM 1 (weak binding)

• additional binding of T cell receptors sends signal to LFA1
• conformational change leads to prolonged affinity and increased contact

How can a naive T cell be activated?

A naïve T cell can be activated only by an antigen presenting cell carrying both a specific peptide: MHC complex & a co-
stimulatory molecule on its surface (B7 on DC binds with CD28 on T cell)

When is there anergy?

specific peptide MHC complex present but no costimulatory signal

• T cell enters non responsive state: anergy

Steps of cell mediated immune response

Antigen recognition: antigens displayed on MHC on DC
Activation: secrete cytokines - increase in lymphocytes - clonal expansion
Differentiation: effector cells eliminate microbes in lymph node or distant site of infection

• promote ab production by B cells
  Memory cells

Functions of effector cells

• activation of macrophages, B cells
• killing of infected target cells, macrophage activation

CMI

The TCR recognizes MHC-associated peptide antigens

• CD4 and CD8 co-receptors recognize the MHC molecules
  • Adhesion molecules strengthen the binding of T cells to APCs
• Receptors for co-stimulators recognize 2nd signals provided by the APCs

Function of CD3 and Zeta

transduce signal of TCR+CD4+CD8 complex: to interior of T cell

What does co stimulation explain?

vaccine adjuvants can increase immune response by costimulation- increased signaling

Stimuli for Activation of CD8+ cells

Graft Rejection

T-cell mediated (MHC mismatch leads to cytotoxic responses)

CD4+ Th1 Fx

Activate macrophages (via IFN-γ); promote cell-mediated immunity

CD4+ Th2 Fx

Help B cells → plasma cells → antibodies (via IL-4, IL-5, IL-13)

CD8+ CTLs Fx

Kill virus-infected or tumor cells

Memory T cells Fx

Long-lived; respond faster upon re-exposure

Th1/Th2 Mnemonic

Mnemonic: “Th1 = One Army (cellular), Th2 = Two Antibodies (humoral)”

💡 Mnemonic: “Superantigens"

Super bad” – cause cytokine storm, not protective immunity.

CD3 & ζ chain fx

Signal transduction from TCR → intracellular signaling leading to T cell response.