Table I. Effects of genetic manipulations of key molecules in the humoral response on GCs, PCs, and Bmem cells
Gene-Targeted DeficiencyHumoral Phenotype
GC Formation and Th CellsAb/AFCs/PCsBmem CellsReferences
CD40No GC formation (measured by histology + PNA after secondary immunization)No switched Ab to TD Ag (not TI)No secondary GC formation(10)
CD40LNo GC formation (measured by histology + PNA)Primary TD, but not TI, IgM responses decreased. Secondary IgG1 absent.Secondary IgG1 absent(11)
CD40L-blockNo GC formation if administered early. Later administration after immunization reduces GC (measured by histology + PNA).After adoptive transfer of primed B cells, IgG1 titers reduced after secondary immunization. BM AFCs were lower-affinity if block occurred after GC formation but no effect on affinity.(4, 7, 12)
ICOSReduced or no GC formation (measured by histology + PNA). Decreased IL-4.IgG1 decreased. Decreased switching.(1316)
ICOSLNo GC formation (measured by histology + PNA). Decreased IL-4.IgG1 decreased. Decreased affinity.Secondary GCs decreased(17, 18)
ICOS-blockDays 5, 6, 7 block: GC cells reduced.Days 5, 6, 7 block: PC number normal but high-affinity reduced.Days 5, 6, 7 block: Bmem cell number normal. Lower-affinity memory compartment. Secondary responses of normal magnitude but lower affinity.(19)
SAPDecreased GC (measured by histology + PNA)Long-lived IgG Ab decreasedMemory decreased (measured by ELISPOT)(20)
LTαNo GC formation (as measured by histology + PNA). Perturbed FDC organization. SHM found.Low doses NP-OVA: drastically reduced Ag-specific IgG1, high doses IgG1 response comparable to WT.(21)
CD80 and CD86GCs form in CD80−/− but very little in CD86−/− (measured by histology + PNA)Decreased Ab and AFCs when both absent(22)
CD86 blockEarly (days 1–3) injection: number of mutations in GC cells reduced.Early (days 1–3) injection: Ab reduced by 50%, late (days 6–10) modest effect.Early (days 1–3) injection: secondary responses were decreased by measurement of Ab.(4)
CD28No GC formation (measured by histology + PNA); B cells formed clusters but did not undergo expansion nor acquire somatic mutations.IgG titers reduced(23)
PD ligandsCapable of GC formation, but GCs declined late in the response.Long-lived PCs decreased, more high-affinity PCs.Bmem cell numbers were comparable to WT or even increased(24)
PD-1Capable of GC formation, but GCs declined late in the response. Increased TFHs but less IL-4 and IL-21.Long-lived PCs decreased, more high-affinity PCs.Bmem cell numbers were decreased(24)
IL-4RαDecreased GCsDecreased AFC and affinity of AFC. Class-switch was impaired.(25, 26)
IL-21 and IL-21RGCs formed but were not maintained (impaired proliferation). TFHs formed, but numbers were variable at different time points. IL-21 acted directly on GC B cells to maintain Bcl-6 expression.Ab was decreased, and class-switch was impaired,Zotos et al. (28): more Bmem cells but of lower affinity. Linterman et al. (29): early memory comparable to WT.(2729)
CD45GCs formed but were not maintainedDecreased Ab production(32)
FASIncreased and sustained GC, which was CD40L dependent.Increased number of, and mutations/gene in, memory.(33, 34)
B cell leukemia-xL TgGC and IgG1+ Ab normalLower-affinity BM AFC and Ab due to retention of low-affinity cells rather than impaired formation of high affinity(6)
Bcl-2 TgIncreased number of GCsIncreased numbers of AFCs; retention of low-affinity splenic AFCs; BM AFC affinity was similar to WT.Increased numbers of Bmem cells due to retention of low-affinity memory cells(3537)
BIMIncreased number of GCsIncreased numbers of AFC; retention of low-affinity splenic AFC; BM AFC affinity was similar to WT.Increased numbers of Bmem cells due to retention of low-affinity memory cells(35)
BCL-6 (hematopoietic chimera)GC formation and TFHs were absentProduced normal levels of IgM and IgG1 until day 14. IgG1 levels decreased over time with few long-lived IgG1 AFCs. IgM remained strong in primary and secondary. Low-affinity IgG1 Ab produced in primary and secondary responses.Bmem cell numbers were normal but no SHM(3840)
Phospholipase Cγ2GCs reducedReduced IgG1 AFCs after primary and secondaryBmem cells reduced(41)
CD21/35GCs reducedLong-lived Ab and AFCs decreased but higher-affinity cells remained(4244)
CD19 hypomorphGCs reduced and failed to progressLoss of long-lived AbReduced secondary response(45)
  • AFC, Ab-forming cell.