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Lymphocyte Development and Survival, H chain VDJ rearranged L chain-V-J rearranging via RAGs -start w/ kappa chain -no surface Ig -intracellular mu chain If non-productive Try kappa on 2nd chrom -then lambda on 1st then 2nd -otherwise, cell loss fewer lost than H-chain rearr., Contain CD4, CD8, CD3 -now contains alpha:beta TCR Negative Selection Can't recognize self peptide:self MHC ->Apoptosis -Majority (ᢗ%), L-selectin on naive T cell-homing (rolling) -binds to sulfated-sialyl-Lewis residue -on HEV cells on GlyCAM and CD34 -binds MAdCAM on mucosal endoth Integrins(LFA-1,VLA-4) on T cells bind tighter -to ICAM(APC), VCAM(endoth) CD2 (T cell) binds CD58 (APC)-synergize binding ->extravasation Naive T cells that recognize Ag are trapped/activated T cell:APC interaction APCs, T cell's ICAM-3, CD2, LFA-1 binds DC's DC-SIGN, CD58, ICAM-1, ICAM-2 LFA-1:ICAM-1 first -stabilized by specific antigen recognition -MHCII:CD8/TCR ->LFA1-ICAM1 increases affinity -association can persist for days ICAM3:DC-SIGN exclusive to naive T:DC T cell Activation T cell enters G1 phase of cell cycle Synth of IL-2 and IL-2 receptor (CD25) (resting T cells w/ low affinity CD25) -can still respond to a lot of IL-2 IL-2 mRNA more stable, x-factors AP-1, NFkB ->more IL-2 Activation->CD25 alpha chain synth -high affinity -binding of IL-2->proceed thru cycle,growth -ɮ-3 divisions/day->thousands in 4-5 days ->diff'ation to armed effector cells, Common Lymphoid Progenitor -Originates in bone marrow -migrate to Thymus Development occurs embedded in stroma -spend up to a week diff'ating -then proliferation 'double negative' thymocytes do not express CD4, CD8, or CD3 -(also includes NK T cells) -in subcapsular region -express pre-TCR and pre-gamma:delta TCR, H chain V-DJ rearranging L chain-germline Large Pre-B cell H chain VDJ rearranged L chain-germline mu chain on surface -pre-B-cell receptor -surrogate L chain ->halt rearrangement -via Igalpha:Igbeta -'allelic exclusion' -express only 1 allele ->proliferation -mostly intracellular, 'double-positive' thymocytes -if receive signals thru pre-TCR -majority -large, active -express CD4, CD8, and CD3 -also contain surface pTalpha:beta -pre-TCR complexed w/ CD3 ->arrest beta rearrangements -analogous to BCR H chain ->cell proliferation ->CD4, CD8 expression -alpha chain rearranges -deletes delta-chain genes 1st -almost always productive -in cortex Small resting Double-Positive Thymocytes Contain CD4, CD8, CD3 -now contains alpha:beta TCR, Heavy chain D-J rearranging L-chain is germline No surface Ig thru large Pre-B Late Pro-B cell H chain V-DJ rearranging L chain-germline, CAN recognize self peptide:self MHC -trying to recognize MHC on stromal cells Stop expressing CD8 or CD4 Immature 'Single-positive' thymocytes -small resting -CD4 OR CD8 positive -and CD3 positive, Recognize MHC-II:peptide on mac ->activate mac to kill intravesic pathogen -via IFN-g, CD40 (kill engulfed bac) -via FasL, TNF-b (apoptosis) ->recruit more T cells via IL-2 ->make more macs in bone marrow via IL-3, GM-CSF ->macs diapedesis via TNF-a, b ->macs chemotaxis to infection via CCL2 Sensitizing signals (to IFN-g)-CD40L/CD40, LPS, memb-bound TNF-a,b IFN-g-acts on TH2 cells to limit prolif DTH Delayed-type Hypersensitivity Rxn -T cells recognize antigen on APCs ->release TNF-b, IFN-g ->recruit plasma cells, monocytes ->inc. vasc. perm ->local swelling in 48-72 hrs ->(+) PPD TB skin test -imp't defense against mycobacteria, Listeria monocytogenes Order of response depends on adhesion molecules 1. E-selectin->PMNs 2. ICAM->monocytes 3. VCAM->T cells Other DTH-type rxns: Contact sensitivity (poison ivy), allograft rejection (diff MHCs), graft vs. host reaction (b. marrow graft) -graft attacks self MHCs