Self/non-self Discrimination

-derived from the lymphoid cell lineage but possess functional characteristics consistent with both innate and adaptive immune functions. -NK cells do not express TCR but do express other components of the TCR complex (eg: some C3 subunits)-

Fc receptors on NK cells recognize opsinizing antibody that coats pathogens of target cells.

-When complexed with antibody pulled from the circulating pool the NK cell will be pre-primed for recognition that is determined by the specificity of the circulating antibodies-active humoral responses will load NK cell with antibodies specific for the pathogen du jour.

-most Fc receptors interact with a gamma subunit signaling partner that contains a cytoplasmic ITAM domain or with a gamma-like subunit that contains an ITIM domain. -Immunoglobulin binding to Fc receptors with ITAM domain initiates activation of macrophages, neutrophils, eosinophils, and NK cells (respiratory burst, secretion of lytic granule contents)-Fc receptors with ITIM or ITAM domains can act as endocytotic receptors, delivering antibody and associated antigen to endocytic compartments where antigen can be processed and presented on MHC

NK cell Killer activity is held in check by the balance of signaling through activating receptors (CD3_, FcR, CD28) that interact with immunoglobulins of other ligands (B7) and inhibitory receptors (KIR) that interact with MHC

-Usually altered self if detected by absence of MHC-I (viral inihibition of TAP, Oncogenic transformation), which normally provides an inhibitory signal to the NK cell.

1. immature T cells arrive from the bone marrow and enter the thymus at the cortico-medullary junction as double negative cells, lacking both CD4 and CD8, as well as the CD3 component of the TCR. 2. TCR rearrangement occurs ing the receptors that may or may not recognize MHC displayed on cortical thymic epithelial cells. 3. Thymocytes become double positive cells (expressing CD4 and CD8) and begin expressing CD3.4. Thymocytes that generate TCRs capable of recognizing MHC-I shut down expression of CD4 and those that have MHC-II TCRs shut down CD85.singly positive CD4+ and CD8+ thymocytes are attracted to the cortico-medullary junction by chemokines produced my macrophages and dendritic cells in the medulla.

1. Positive selection for thymocytes expressing rearranged TCRs that bind self-MHC (presenting self-peptide) on cortical thymic epithelial cells. Cells that can interact with MHC survive, those that can't apoptose; a postivie survival signal. Commitment to CD4 or CD8 espression. 2. Negative selection for thymocytes that express rearranged TCRs that bind self-peptides presented by self-MHC on medullary epithelial cells (AIRE transcription factor, autoimmune regulator), macrophages, or marrow-derived dendritic cells. Cells that interact weakly are matured, naive CD4+ or CD8+ T-cells.

1. thymocytes expressing TCRs that interact weakly or not at all with self-peptides presented by self-MHC pass out of the thymus as CD4+ or CD8+2. thymocytes expressing TCRs that interact with intermediate strength with self-peptides presented by self-MHC are selected to become Treg cells

1. the peptides are recognized by TCRs that interact with self-peptides on self-MHC may be sequestered in immunoprivileged tissues. 2. self-peptides recognized by TCRs may elicit T-cell anergy because the self peptide is not present in the context of an inflammatory response where essential activating co-receptors are also expressed. T-cell anergy results from decreased DAG production, perhaps through reduced PI-PLC levels, and from subsequent reductions in MEK/ERK signaling through Ras, which leads to lower growth signals. 3. Treg cells supress anti-self responses. Treg cells can recognize self-peptides presented by self-MHC on antigen presenting cells and, in response, secrete anti-inflammatory cytokines (IL-4, IL-10, TGF-b) that inactivate the APC and also inhibit T cell responses.

1. B-cell tolerance is inherent in the generation of T-cell tolerance since a lack of Th cells with self-peptide specificity ensures that B cells with similar specificity cannot be activated. 2. B-cell tolerance is also achieved by B-cell anergy. B-cell anergy can be induced by an appropriate level of BCR signaling (Goldilocks). Strong Signaling induced by a multivalent binding of self-antigen to BCR results in B-cell death. Intermediate signaling by soluble, self-antigen that may induce moderate BCR cross-linking generates an anergic response due to lack of co-stimulatory Th input. 3. B-cell anergy results from altered signaling very early in the BCR signaling cascade (perhaps through altered CD22-SHP1 function)