T and B cell Responses

T Cell Origins

originate from the bone marrow and migrate to the thymus, positive and negative selection occur in the thymus

Positive Selection for T Cells

occurs in thymus, T cell recognizes self-MHC

Negative Selection for T Cells

occurs in the thymus, strong self-reactive T cells are eliminated

Clonal Selection for T Cells

linear peptide-MHC activates only T cells with the matching TCR specificity, activated T cells differentiation into effector and memory cells

CD4 T Cells

T helper cells, have several subsets driven by different cytokine environments when differentiation occurs

CD8 T Cells

cytotoxic activated T cells, kill infected and tumor cells presenting antigen on MHC I

3 Signals for T Cell Activation

antigen recognition, co-stimulation, cytokines

IL-12

APC-derived cytokine that influences Th1 differentiation

Th1 Cells

a CD4 helper T cell activated by IL-12, activates macrophages and promotes cell-mediated immunity

IL-4

APC -derived cytokine that differentiates Th2 T cells

Th2 Cells

a CD4 helper T cell and promote B cell activation and antibody production, differentiated by IL-4

TGF-beta and IL-6

APC-derived cytokines that differentiate Th17 cells

Th17 cells

a CD4 helper T cell that recruits neutrophils and promote inflammation against extracellular microbes, differentiated by TGF-beta and IL-6

IL-2

cytokine used for autocrine signaling on T cells for promoting T cell proliferation

B7

a surface molecule on APC that binds CD28 on T cells for co-stimulation

CD28

receptor on Th cells that bind B7 from APC for co-stimulatory signal

CD40

surface protein on APCs that aid in co-stimulatory signals for Th cells by binding CD40L

CD40L

surface ligand on Th cells that binds CD40 on APCs and aids in co-stimulatory signaling

Perforin and Granzymes

after forming a synapse with the target cell, the CTL releases these enzymes to make pores in the cell and destroy the cell to trigger apoptosis

FasL

surface protein on CTLs that binds Fas on target cells to trigger apoptosis

Fas

surface protein on target cells that binds FasL on CTLs which triggers apoptosis

Peripheral Tolerance

occurs as a safety feature for T cells, fi they see antigen without the appropriate co-stimulation the cell will become anergized

Anergy

functional non-responsiveness, occurs in T cells that do not receive co-stimulation

Langerhans’ Cells

cells that patrol in the skin, capture and ingest antigen, and migrate to lymphoid tissue where they differentiate into dendritic cells to present antigens to T cells

Mycobacteria

bacteria that infects macrophages, these macrophages present antigen to Th1 cells which activate them to produce IFN-gamma, which activates the macrophage to kill the intracellular pathogen

Exogenous

originates from outside the cell, shown on MHC II to activate CD4 T cells for a humoral response

Endogenous

originates inside the cell, shown on MHC I to activate CD8 T cells for cell-mediated killing

MHC II

binds linear exogenous peptide fragment and activates CD4 T cells, produced in the rough ER and protected by the invariant chain (Ii) until a peptide fragment outcompetes it in a vesicle

Invariant Chain (Ii)

protects MHC II binding site in the RER, is outcompeted by exogenous antigen protein fragments within transport vesicles

TAP

protein channel in the RER that allows endogenous antigen fragments to be imported and match with MHC I

MHC I

made in the rough ER and aided in loading endogenous antigen by the TAP protein, once bound to antigen it migrates to the membrane for presentation and the activation of CD8 T cells

Cross Presentation

mainly occurs in dendritic cells, occurs when an exogenous antigen is taken into a cell and escapes the endosome to enter the cytosol, therefore finding an MHC I match and being presented in the endogenous pathway

Major Histocompatibility Complex (MHC)

a group of linked genes that encode molecules involved in antigen presentation

Haplotype

set of linked alleles inherited together from one parent

MHC I Structure

antigen-binding groove formed by alpha 1 and 2 domains of the heavy chain to present peptides to CD8 T cells, alpha chain is polymorphic while beta chain is less polymorphic

MHC II Structure

antigen-binding groove is formed by the alpha 1 and beta 1 domains of the heavy chain to present peptides to CD4 T cells, all genes are highly polymorphic

MHC II Species Differences

rodents: always on DC, macrophage, and B cell, can be induced on others

dog/cat/horse/mink/pig: expressed on resting T cells

Pig and Man: also express on kidney cells

MHC III

non-polymorphic genes, not involved in antigen presentation, functions include complement, TNF, and heat shock proteins

CD79A/B

transmembrane proteins on B cells that aid in transmitting an intracellular signal when neighboring BCRs crosslink in response to an antigen, ITAM signaling motifs

ITAM Signaling Motifs

protein segments that exist on the intracellular portion of BCRs and CD79A/B that aid in transmitting the intracellular signal

T-Independent B Cell Activation

multiple BCRs crosslink due to a repetitive antigen, CR2 binding C3d enhances signal, causes B cell to undergo clonal expansion and differentiates into an IgM plasma cell, usually triggered by a polysaccharide antigen (no affinity maturation and no memory formed)

T-Dependent B Cell Activation

BCR binds antigen and internalizes and processes it onto an MHC II molecule, this MHC II is then recognized by Th2 cells, CD40-CD40L binding from T cell provides extra stimulus for B cell along with cytokines, causes B cell to undergo clonal expansion and class switching → somatic hypermutation and affinity maturation in germinal centers, forms memory and plasma cells

Class Switching

occurs in the germinal center on the BCR heavy chain locus by recombination of the constant region genes, initiated by AID enzyme after activation by CD4 T cells

Activation-Induced Cytidine Deaminase

enzyme responsible for class switching on the BCR heavy chain locus, activated once B cell receives help from T cells

IFN-gamma

cytokine that induces B cell to class switch from IgM to IgG

IL-4

cytokine that induces B cell to class switch from IgM to IgE

TGF-beta

cytokine that induces B cell to class switch from IgM to IgA

Somatic Hypermutation

point mutations are induced on the variable region of the BCR in germinal centers, higher affinity receptors are allowed to proliferate while weaker affinity receptors undergo apoptosis

Affinity Maturation

selection of B cells in germinal centers after somatic hypermutation to allow the highest affinity B cells to proliferate and killing lower affinity B cells

Follicular Dendritic Cells

specialized cells in germinal centers that have intact antigen on their surface and B cells must compete to get that antigen and process it for Tfh stimulation

Tfh Cells

class of CD4 T cells that go to germinal centers to find B cells presenting antigens on MHC II that match the TCR, differentiates B cell into memory or plasma cells

Fc gamma Receptor

receptor on macrophages and monocytes that allow the cell to phagocytose pathogens bound by IgG, binds CH2-CH3 region on the IgG heavy chain

Mass Concentration

the total immunoglobulin or individual isotype mass, reported in mg/dL or g/dL

Titer

measure of antigen-specific antibodies, calculated by serial dilutions and is reported as the reciprocal of the dilution (if the dilution is 1:216, then it is 216)