immunology

Adaptive Immunity and the MHC System

Core Components

• The Sensor: A diverse library of T-Cell Receptors

• The Display: The standard MHC System

• Together these components create a precision two-part system for adaptive immunity recognition

V(D)J Recombination Mechanism

• 12/23 Rule: Governs V(D)J recombination which generates antibodies and T cell receptors

• Recombination only occurs between gene segments containing RSS (Recombination Signal Sequences)

• RSS contain spacer regions: one 12-bp spacer and one 23-bp spacer

• P-nucleotides: Created by hairpin cleavage during recombination

• N-nucleotides: Randomly added by TdT enzyme (Terminal deoxynucleotidyl transferase)

Severe Combined Immunodeficiency (SCID)

Overview

• Definition: Total defense failure; a broken system where T cells and B cells are both missing

• Severity: Extremely severe—without immune cells, even a common cold can lead to death

The Bubble Boy Mnemonic

A memory aid for SCID characteristics:

• B - B cells are absent

• U - Unable to fight any germs

• B - Bone marrow transplant is the primary cure

• B - Boys are more commonly affected (X-linked inheritance pattern)

• L - Lymphocytes (T, B and NK cells) are missing

• E - Early diagnosis is a pediatric emergency

Clinical Presentation and Diagnosis

Signs of SCID in infants:

• Baby doesn't grow fast or gain weight

• Digestive issues

• Thrush (yeast infection in mouth or diaper area that won't resolve)

Diagnostic test:

• TREC Test: Newborn screening for B cells

Related SCID Conditions

• RAG1/2 Deficiency

• Omenn Syndrome

• SCIDA

• ZAP70 Syndrome

MHC Antigen Presentation Pathways

Exogenous and Endogenous Pathways

• Detailed comparison of pathways available

• Cross presentation: Method necessary for immune response coordination

Dendritic Cell Function

• DC licensing and cross priming by TH (helper T) cells

• Role in unconventional MHC activation

• Conventional vs. Non-conventional MHC presentation mechanisms

Classical vs. Non-Classical MHC Molecules

• Classical MHC I molecules: Presentation pathway details

• Classical MHC II molecules: Presentation pathway details

• Non-classical accessory molecules: Supporting presentation mechanisms

• MHC II pathway: Specific presentation route

• Presentation of non-peptide molecules through non-protein antigens

CD1 Family and Lipid Antigen Presentation

CD1 Gene Family

• Five human CD1 genes: CD1a, CD1b, CD1c, CD1d, CD1e

• Polymorphism: Low polymorphism across the family

• Structural similarity: Structurally similar to MHC I molecules

• Function: Present lipid antigens to T cells (mechanism involves antigen processing)

CD1-Mediated Lipid Antigen Presentation by Cellular Compartment

• Group 1 CD1 molecules: CD1a, CD1b, CD1c

• CD1a: Processing location and routing details

• CD1b: Routes through late endosomes and lysosomes

• CD1c: Routes through intermediate endosomes

• MAIT Cell Recognition and Function:

• APC infected with bacteria (e.g., Salmonella) produces B2 metabolites.

• MR1 molecule in the ER binds these metabolites.

• MR1-metabolite complex presented on the cell surface recognized by MAIT cell TCR.

• MAIT cells require antigen recognition and cytokine signals for activation (two-signal hypothesis).

• Activated MAIT cells can act as helper cells by secreting cytokines, primarily interferon-gamma, to combat intracellular pathogens.

• MAIT cells can also directly kill infected cells displaying MR1-metabolite complexes.

• TAP transporter is necessary for metabolite transport into the ER for MR1 presentation.

• Ligands for MR1 are produced by pathogenic organisms:

• Gram-negatives: Escherichia, Shigella, Salmonella, Clostridia

• Mycobacterium

• Gram-positives: Streptococcus, Staphylococcus

• Yeast: Candida, Aspergillus

• Sarcomycin

• Upcoming Topics & Exam Information:

• Discussion will transition to immune suppression molecules.

• CD1 and MR1 presentations will not be included in short answer questions.

• Immune Suppression Molecules (HLA-E and HLA-G):

• MHC-encoded, non-classical molecules.

• Present a restricted set of self-peptides.

• Do not trigger activation on their own.

• Involved in NK cell licensing/education.

• NK Cell Licensing/Education:

• NK cells mature and undergo education, primarily in the thymus.

• Learn to recognize self-peptides presented on thymic cells to set activation thresholds.

• Signaling through inhibitory receptors leads to licensing/education.

• Licensed NK cells are more sensitive to activating signals.

• Activation results in synapse formation and killing of target cells, similar to cytotoxic T cells.

• Education establishes an inhibition threshold; exceeding this threshold with activating signals leads to killing.

• Activation can occur via:

• Absence of inhibitory signals (e.g., loss of Class I molecules on target cell).

• Overcoming inhibitory signals with sufficient activating signals.

• Two types of education:

• Classical education: NK cells learn from self-peptides presented by classical MHC molecules (HLA-A, B, C).

• Non-classical education: NK cells learn from self-peptides presented by non-classical MHC molecules.

• HLA-E and Its Ligands:

• Encoded within the MHC, non-classical molecule.

• Ubiquitously expressed.

• Binds a specific and restricted subset of peptides.

• Binds the "signal peptide" cleaved from classical HLA class I molecules by signal peptide peptidase (SPPase) during their ER processing.

• This cleaved signal peptide is then targeted to the proteasome, and fragments are transported via TAP into the ER to bind HLA-E.

• Binding of these self-peptides is required for HLA-E to be shuttled to the cell surface.