Immunology T cell activation and MHC 1, 2, 3

Where do immature lymphocyte precursors derive from?

Pluripotent stem cells in the bone marrow.

What is the difference between antigen-independent and antigen-dependent development of lymphocytes?

Antigen-independent occurs in primary lymphoid organs and includes receptor diversity generation and central tolerance. Antigen-dependent occurs in secondary lymphoid organs where lymphocytes respond to foreign antigen.

How are lymphocytes targeted to new locations during development?

By expressing new cell surface adhesion proteins that correspond to endothelial surface receptors.

What is central tolerance?

The process by which self-reactive lymphocytes are eliminated or inactivated in primary lymphoid organs to prevent autoimmunity.

At what stage does central tolerance occur?

During antigen-independent development in primary lymphoid organs.

What is clonal selection?

Only lymphocytes with receptors that bind strongly to a foreign antigen are activated, proliferate, and differentiate into effector cells.

What do B cells become after clonal selection?

Plasma cells that secrete antigen-specific antibodies.

What do T cells become after clonal selection?

T helper cells that secrete cytokines or cytotoxic T cells that kill infected host cells displaying foreign antigens.

How many identical receptors does each lymphocyte express on its surface?

Thousands of identical receptors.

Can a lymphocyte express more than one MHC receptor at the same time?

More than one MHC receptor can be expressed, but only one can function at a time.

What are the BCR gene clusters and their components?

IGK (kappa light chain), IGL (lambda light chain), IGH (heavy chain); each contains V (variable), J (joining), D (diversity, heavy only), and C (constant) regions.

What are the TCR gene clusters?

Alpha/beta chains and delta/gamma chains.

What mechanisms generate receptor diversity?

Germline diversity (multiple V, D, J copies), combinatorial diversity (different VJ/VDJ combinations), junctional diversity (variation at joining sites), multiple light/heavy chain combinations, and somatic hypermutation with affinity maturation.

How does somatic hypermutation contribute to receptor diversity?

Point mutations occur at a high rate in the V region, and cells expressing higher-affinity receptors are preferentially selected.

What is gene recombination in receptor diversity?

Random mixing and matching of gene segments: light chain uses V and J; heavy chain uses V, D, and J.

What additional processes create BCR diversity?

Gene recombination, somatic mutation, gene conversion, base insertion/deletion, and editing.

What processes create TCR diversity?

Gene recombination and gene conversion.

What is exogenous antigen?

Antigen originating outside the host cell, best eliminated by B cells through a humoral response.

What is endogenous antigen?

Antigen originating inside the host cell, best eliminated by cytolytic T cells through a cell-mediated response.

Why is antigen processing needed to initiate an adaptive immune response?

Because T cells can only recognize antigen when it is processed into peptide fragments and presented on MHC molecules.

What happens when a cell displays foreign antigen on MHC I?

CD8+ cytotoxic T cells are activated to kill the host cell.

What happens when a cell displays foreign antigen on MHC II?

CD4+ helper T cells are activated to secrete cytokines, helping B cells and macrophages mount a response.

What cytokines activate T helper 1 cells?

IL-12 and IFN-gamma (also activates macrophages).

What cytokine activates T helper 2 cell differentiation?

IL-4.

What are the steps in processing exogenous antigen?

Antigen-presenting cell (APC) engulfs material by endocytosis, breaks it into linear epitopes, loads them onto MHC II, and presents to CD4+ T helper cells.

What type of cells can process and present exogenous antigen?

Professional antigen-presenting cells

What are the steps in processing endogenous antigen?

Proteins are tagged by ubiquitin, digested by a proteasome, peptides transported to the rough ER by TAP (transporter associated with antigen processing), bound to MHC I, and displayed on the cell surface.

What is the main role of MHC class I molecules?

To present peptides (mostly self, but also viral/tumor antigens) to CD8+ T cells.

Which cells express MHC class I molecules?

Most nucleated cells

What are the different loci of MHC class I molecules and their functions?

Class Ia: hypervariable antigen binding; Class Ib: conserved binding site; Class Ic: does not bind antigen, NK and T cell communication; Class Id: binds to PAMPs.

Where are MHC class II molecules expressed?

On professional APCs such as macrophages, dendritic cells, and B cells.

What are the structural features of MHC class II molecules?

Alpha 1 and 2, Beta 1 and 2 subunits; hypervariable region at Alpha 1 and Beta 1.

What are the highly polymorphic loci of MHC class II molecules?

DP, DQ, and DR.

What are the non-polymorphic loci of MHC class II molecules?

DO, DM, and DOB.

What is the main role of MHC class II molecules?

To present processed exogenous antigens to CD4+ T helper cells.

What is the role of MHC class III molecules?

They are non-polymorphic and linked to innate immunity, encoding complement proteins, TNF, and heat shock proteins.

How do MHC molecules differ from BCRs and TCRs in specificity?

MHCs are not highly specific; they bind peptides based on particular residues and can present a wide range of peptides, but only one at a time.

Which MHC classes are evolutionary stable?

Class II and III.

Which MHC class is more variable by species?

Class I.

What advantage does MHC heterozygosity provide?

Heterozygotes are more likely to have the right fit for any given antigen, increasing immune success, but with a higher risk of recognizing self-antigen.

How does increased MHC diversity benefit populations?

More gene variants increase the likelihood that a population can resist a wide range of pathogens, slowing the spread of disease.

What type of foreign molecules are the best antigens to stimulate an immune response?

Large, complex foreign molecules.

What three signals are required to activate a T helper cell?

1) TCR recognition of antigen on MHC II, 2) Co-stimulatory signal from an APC (B cell, macrophage, dendritic cell), 3) Proinflammatory cytokines (IL-1, IL-12) from APC.

What three signals are required to activate a CD8+ T cell?

1) TCR recognition of antigen on MHC I, 2) Co-stimulatory signal from an APC, 3) Proinflammatory cytokines (IL-12) from APC.

What happens in peripheral tolerance?

When a non-APC presents antigen, the T cell is silenced instead of activated.

Which type of MHC do CD4+ T cells recognize?

MHC class II.

What is the structure of the T-cell receptor (TCR)?

A heterodimeric quaternary structure.

What cytokines do T helper 1 cells secrete and what immunity do they mediate?

IL-2, IL-12, and IFN-gamma; they promote cell-mediated immunity.

What cytokines do T helper 2 cells secrete and what immunity do they mediate?

IL-4, IL-5, IL-9, and IL-13; they promote humoral immunity.

What cytokines do T helper 17 cells secrete and what immunity do they mediate?

IL-17, IL-21, and IL-22; they promote defense against fungal infections.

What cytokines do T regulatory cells secrete and what is their function?

IL-10 and TGF-beta; they suppress immune responses.

What are Langerhans cells and what do they become in secondary lymphoid organs?

Skin-resident phagocytic cells; once in secondary lymphoid organs they stop phagocytosis and become dendritic cells.

What molecules do dendritic cells express at high levels?

MHC I, MHC II, co-stimulatory molecules (B7), and adhesion molecules.

What are the three stages of cytolytic T cell function?

1) Cell-cell adhesion with the target host cell, 2) Secretion of cytoplasmic granules into the target, 3) Disengagement as the host cell undergoes apoptosis.