Lymphopoeisis Flashcards
Lymphocyte production areas
Young fetus: liver and spleen
Late fetus-on: bone marrow
General Outline of B cell hematopoeisis
HSC -> CLP (not CMP) -> Pro-B (not T lineage) -> Early Pre-B -> Late Pre-B -> Immature B cells
2 Proliferative Steps in B Cell Hematopoeisis
CLP -> ProB and Early Pre-B -> Late Pre-B
True B Cells
Actively involved with synthesizing intact Ig, Immature B cells are the first ones
2 Cell Surface Markers on Pro-B that Identify As B (and function)
CD19 - costimulatory of B cells
CD45R - phosphatase to maintain signalling pathway
2 Rag Activity Steps in B Hematopoeisis
ProB and Early PreB: VDJ of HC to create HC mu
Late PreB and Immature B: VJ of LC to create LC lambda and kappa
B Cell Hematopoeisis Checkpoint
Between Early/Late Pre-B. Surrogate LC has to bind to HC expressed on surface and form preBCR which can signal. Extent of preBCR formation dictates clonal proliferation. It also turns off Rag and SL, but as SL decreases, so does preBCR, so Rag turns on again at Late Pre-B/Immature B transition for LC recombination
2 Parts of Surrogate LC
VreB - equivalent to V of LC
lambda5 - C of LC
Bone Marrow Stroma Proliferative Effects
Release cytokines/other factors which bind to c-kit and IL-7R on Pro-Bs to drive proliferation at low levels. C-kit is lost for PreBs though because it wants preBCR to be the main driver of proliferation
2 Differences b/w Immature and Mature B Cells
Just IgM vs. IgM and IgD
Most autoreactive vs. most not
2 B Cell Tolerance Mechanisms
Self Ags exposed, if react strongly just undergo clonal deletion/death, if react weakly undergo receptor editing to salvage - turn LC recomb back on until it either dies or is no longer self reactive
3 Types of B Cells
B-1: Fetal/neonatal, first line of defense good at responding to common bacterial pathogens but can cause leukemias B-2: Normal Bs Marginal Zone (MZ) Bs: in white pulp of spleen, good at responding very quickly to common Ags on bloodborne pathogens (1st line of defense there)
3 Steps of T Cell Development and Location
Commitment - rearrangement/expression of TCR - subcapsular region
TCR Pos/Neg Selection - TCR repertoire established - cortex
Maturation - produce functional CD4/8 Ts - medulla
2.4 Cellular Components of Thymus
Thymocytes - developing T cells
Stroma which produce necessary signals: Nonlymphoid (fibroblasts, epithelial, pos selection) and lymphoid (dendritic cells neg selection, macs)
Hassall’s Corpuscles
In thymus to get rid of dead/dying cells
DiGeorge Syndrome
Thymic aplasia, don’t ever develop it so you don’t get T cell production really
T Cell Development, CD4/8 Containing Aspects, and Proliferation
Proliferate from precursors to double negs in subcapsular
Proliferate to double pos for R selection in cortex
Heavily selected against so numbers drop to medulla and only CD4+ or CD8+
2 Effects of IL-7
Stimulates bone marrow precursor cell to Tc (and also can stimulate that to a TCRgamma/delta) during commitment
TCR Recombination
Gamma and beta on different chroms, just need to recombine VJ
Alpha/delta on same chrom, either no alpha rearragement or it deletes delta
3 TCR alpha/beta and gamma/delta differences
More adaptive vs. innate
More numerous vs. less
Peripheral lymphoid tissues vs. GI/resp
Beta Selection
Ensures a lot more alpha/beta by only needing one rearragement (beta) and then undergoing second round of intense proliferation with a productive arragement
X-Linked Severe Combined Immunodeficiency Disease (X-SCID)
Failed IL-7 signaling gives shitty cytokine R gammac sub, necessary for IL Rs including IL-2, and so no T or NK cells
3 Important Aspects of Commitment
IL-7 dependent expansion of precursor cells
Rearragement of TCR beta/gamma/delta genes
Second wave of expansion for Ts w/ TCRbeta mediated by pre-TCR (beta selection)
Positive and Negative Selection in General
Positive: only Ts which bind MHC can live or else death by neglect
Negative: Ts that bind too strongly killed.
Together get only weakly bound, self tolerant Ts
CD4/CD8 Selection
Exposed to epithelial MHCs. If weakly recognizes MHC II, Th-POK produced to cause CD4>CD8. If weakly recognizes MHC I, no Th-POK produced and CD8>CD4. If no binding, death by neglect. If strong binding (later against DC-presented self Ags), negative selection and death.
2 Sources of Negative Selection
DCs/Macs presenting broken down self peptides
Thymic medullary epithelial cells expressing autoimmune regulator (AIRE), a transcriptional activator which produces tons of tissue-specific prots like insulin
MHC Restriction
Result of positive selection - if that CD doesn’t bind, it’s not gonna be that kind of mature cell
Bare Lymphocyte Syndrome
Lack of MHC II expression on thymic epithelial cells and APC, so no positive selection and no mature CD4+ Ts for generalized immunosuppression
Treg Function
To inhibit autoreactive Ts that escape neg selection via inhibitory cytokines (IL-10, TGFbeta) and inhibitory Rs (CTLA4)
Treg Production
Stimulated by *IL-2R and depend on transcription factor Foxp3
X-Linked Autoimmune Immunodeficient Syndrome
Foxp3 gene mutation so no Tregs and multiorgan inflammatory infiltrates cause wasting away
4 Aspects of Thymocyte Maturation
Express only CD4 or 8
Increase TCR
Acquire functional potential (CTL or cytokine secretion)
Acquire homing Rs necessary to leave thymus and enter tissues
