• individual lymphocytes carry receptors of only one specificity, the specificity of each lymphocyte is different, thus the millions of lymphocytes in the body give rise to millions of different specificities
• How is this diversity generated?
• Randomly combine variable (V), diversity (D), and joining (J) gene segments for both the a and b chains of the TCR which gives rise to millions of combinations
• What does the body do with this diversity?
• The immune system uses this diversity to distinguish between hundreds of thousand autoantigens (which are not to be attacked, but tolerated) and between hundreds of thousands of foreign antigens (which are to be attacked)
• Thus, It develops Tolerance for autoantigens and an immune response against foreign antigens

• Abstraction level 1: (2 independent criteria are established for "Foreign"):
• Ag receptors on B cells bind antigen directly so B cells assess the "shape" of antigens
• Ag receptors on T cells do not bind antigen directly: they bind peptide fragments of the antigen presented on MHCs therefore T cells assess content (amino acid sequences) of proteins
• Abstraction level 2:
• In different individuals, T cells assess different peptide fragments of the same antigen
• Individual A Þ MHC allele A Þ recognizes peptide x-1
• Individual B Þ MHC allele B Þ recognizes peptide x-2
• Individual C Þ MHC allele C Þ recognizes peptide x-3
• each allele has different binding affinities
• my T cells have alleles that are only specific to me; all the other antigen in the universe = foreign
• T cells jump from lymph node to lymph node and all antigen info is presented in these lymph stations
• Abstraction level 3:
• T cells can judge what happens inside the cell, they survey intracellular protein synthesis
• Extracellular proteins are displayed in APC’s via MHC II to CD4+ cells
• Intracellular proteins are displayed by all cells via either MHC I or MHC II to CD8+ and CD4+ cells respectively
• Cell displays all proteins it processes, there is no privacy
• Therefore, T cells come in contact with all protein in the body and can determine if its normal, bacterial, or viral

• Stem cell (bone marrow) Þ random T cell receptor rearrangements Þ Immature T cell (thymus)
• All proteins need to be present in thymus in order to teach the T cells what is self (1^st reading)
• Three categories of immature T cells:
• No affinity (T1): not capable of interacting with the MHC in the body therefore useless and die by neglect
• High affinity (T2): too reactive, would destroy the body therefore activation cell death
• Intermediate affinity (T3): mature and go on Þ leave thymus (positive selection)
• 95% of all T cells in thymus undergo negative selection (death)
• negative and positive selection is an active self checking process
• If virus is present in thymus at this time, body thinks it is self and will cause a big problem (ie HIV)
• Why have these restrictions?
• KEY: we want to produce T cells that recognize the MHC molecule but not react with self antigen
• Thus no affinity is lost because they do not react with MHC molecule
• High affinity is lost because it reacts with MHC molecule but also reacts with self antigen
• Intermediate affinity remains because it reacts with MHC molecule but does not react strong enough with antigen to cause a problem
• The intermediate T cells mature Þ leave thymus Þ circulate for 10 years and die unless they encounter an antigen specific for its TCR

• Because T cells are selected on the MHC alleles expressed in a host, T cells selected in an "A" type host, will recognize antigen only presented on "A" type APCs
• If the host has "A" and "B" type MHC alleles, the T cells will recognize antigen presented on "A" and "B" type APCs
• This is important for bone marrow transplants
• If host is MHC restricted to "A" and "B" types and receives a transplant from an "A" and "B" type donor, his T cells will be able to recognize antigen presented on the donor’s APCs
• If host is MHC restricted to "A" type only, and receives a transplant from an "A" and "B" type donor, his T cells will be able to recognize antigen presented on the donor’s "A" type APCs only
• If host is MHC restricted to "D" type only, and receives a transplant from a "C" type donor, his T cells will not be able to recognize any antigen presented on the donor’s APCs

• In bone marrow, stem cell does not express TCR, CD4, or CD8 Þ double negative
• In cortex of thymus, immature T cell expresses TCR and both CD4 and CD8 Þ double positive
• In medulla of thymus, if immature T cell touches an MHC II cell Þ expresses CD4 only (single positive)Þ matures and enters periphery as CD4+ T cell
• In medulla of thymus, if immature T cell touches an MHC I cell Þ expresses CD8 only (single positive) Þ matures and enters periphery as CD8+ T cell
• Thus T cells learn their identity
• This defined sequence of phenotype changes (from DN to DP to SP) is diagnostic of some tumors
• Some tumors freeze at one of these stages (ie double positive)

• Naïve T cells leave thymus and recirculate among lymph nodes seeking "their" antigens (the one their TCR is specific for)
• Thymus Þ blood Þ lymph nodes (duct stations, receptor for: L-selectin which seeks the T cell) Þ afferent lymphatics Þ thoracic duct Þ back to the blood
• With this cycle, one T cell can search all lymph node stations in a single day
• Specific T cells recognize antigens on APC, and if APC is activated (ie at site of infection) Þ immune response Þ proliferation and differentiation into effector/memory cells
• If APC is resting (ie normal uninflamed tissue), antigen recogntion will cause the T cell to die (peripheral tolerance)
• What determines which response will occur (immune response vs peripheral tolerance)?
• activated APC (infection) Þ carries foreign peptide in MHC and expresses B7 on its cell surface Þ mature T cell specific for the foreign peptide binds to MHC and T cell-CD28 binds to the B7 therefore Receives 2 signals Þ proliferation/differentiation, immune response, produce memory T cells
• resting APC (no infection) Þ carries tissue specific self peptide in MHC and does not express B7 on its cell surface Þ mature T cell specific for the self peptide binds to MHC but T cell-CD28 cannot bind to B7 therefore Receives 1 signal Þ suicide ie peripheral tolerance
• Memory cells circulate throughout their lives (several decades) surveying every tissue of the organism. If they reencounter "their" antigen in a tissue, they will locally release cytokines, Th1 cells secreting Th1 cytokines and Th2 cells secreting Th2 cytokines. These cytokines trigger a local reaction, here Th1 cytokines cause macrophage attraction and activation (delayed type hypersensitivity) which helps fight the pathogen. When the T cell response is erroneously directed against a "self antigen", T cell-mediated autoimmune disease will result
• Memory T cells lose L-selectin expression so don’t go to the lymph nodes anymore
• They express adhesion molecules (LFA-1 Þ ICAM-1; CD-44; CD2 Þ LFA-3) Þ go to periphery now and look for antigen
• Memory T cell circulation: attach to capillary Þ diapedesis Þ no antigen in tissue Þ afferent lymph Þ lymph node Þ efferent lymph Þ blood
• OR attach to capillary Þ diapedesis Þ antigen is present Þ secretes cytokines and inflammatory response Þ delayed type hypersensitivity (24-48 hrs)

• a cross-reactively activating memory T cell has a lower activation threshold
• due to its lower threshold, it is more easily activated and the memory T cell is stimulated by auto-antigen which the naïve T cell neglected
• as mentioned above, when the naïve T cell encounters a resting APC Þ receives 1 signal Þ does not reach threshold Þ does not elicit response and dies
• when naive T cell encounters an activated APC Þ receives 2 signals Þ reaches threshold Þ elicits response against foreign pathogen Þ forms memory T cells
• These memory T cells have a lower threshold compared to the naïve T cells, instead of needing 2 signals to elicit a response, only need 1 signal to elicit a response
• Therefore, if memory T cells result from a foreign antigen that is very similar to a self-Ag, the memory T cells will bind to the self-Ag presented on a resting APC Þ memory T cell receives 1 signal Þ elicits an autoimmune response
• Priming (for example, by cross reactive antigen) is required for induction of autoimmunity
• Priming occurs when a host is infected by a foreign peptide that is very similar to self-peptide
• Instead of ignoring the self peptide as before (tolerance), the primed T cell attacks the self-peptide (autoimmunity)

• multiple sclerosis
• crossreactive stimulation activates T cells (TH1) that can now recognize the autoantigen, myelin basic protein (MBP), which is only present in the CNS
• these T cells recognize MBP in the CNS and cause a DTH-type inflammatory reaction there: macrophages become activated and cause the damage to the tissue
• Demyelination of axons results leading to decreased nerve conductivity and paralysis
• Type 1 diabetes: target antigen is glutamate decarboxylase (GAD)
• Rheumatoid arthritis: target antigen is collagen
• Autoammune diseases are frequently associated with a certain HLA allele
• Minimal requirements for developing T cell-mediated autoimmune disease:
• crossreactive infection
• HLA-allele
• Magnitude of T cell response (clonal size of effector cells)
• Th1 quality of response (Th2-type autoimmune T cell response can even protect from autoimmune disease)

Protective autoimmunity – (by autoreactive Th2 cells)

• Th1 cells secrete pro-inflammatory signals: IFN gamma, LT, IL-2
• Th2 cells secrete anti-inflammatory signals: IL-4, -5, -10, -13
• Mechanism of protection by autoreactive Th2 cells
• Bystander suppression (IL-4, IL-10, IL-13, TGF) in target organ (not antigen specific)
• Th2 bias in target organ (not antigen specific)
• Exhaustion of uncommitted precursor cells (antigen specific)
• B cell mediated autoimmunity
• diseases mediated by:
• destruction Þ attack antigen and destroy
• masking surfaces without destruction (ie myasthenia gravis Þ block ACh receptors at neuromuscular junctions)
• mimic hormones (ie Grave’s disease Þ thyrotoxicosis Þ increased thyroid horm Þ protruding eyes)