Upstream eventImpaired T cell activation
Impaired Ab production
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of IL-1 signaling||adjacent||High||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
Key Event Relationship Description
‘Help’ to B cells is not a single product of TFH cells and not even a single process. T cell help to B cells can be divided into seven distinct functions, proliferation, survival, plasma cell differentiation, somatic hypermutation, class-switch recombination, adhesion and attraction. These seven different forms of help are all contributors to TFHcell–B cell interactions, and each process consists of multiple pathways. Furthermore, some molecules have a role in several different forms of help.
Evidence Supporting this KER
The simplest B cell help function that is provided by TFHcells is the induction of B cell proliferation. CD40L is the most prominent protein expressed by TFHcells that contributes to pro-mitotic signalling in B cells64. Survival signals from TFH cells are also crucial, as germinal centre B cells are exquisitely pro-apoptotic. IL-4 produced by TFHcells triggers pro-survival signals to germinal centre B cells via the IL-4 receptor complex. Somatic hypermutation is central to germinal centre biology and the primary purpose of germinal centres is to facilitate affinity maturation of B cells via sequential rounds of immunoglobulin gene mutation and selection. The enzyme activation-induced cytidine deaminase (AID) induces the DNA damage in the immunoglobulin genes that is then converted into mutations by DNA repair enzymes. BCL-6 must be co-expressed with AID by the germinal centre B cell to repress the DNA damage response programme that would otherwise trigger self-destruction of the cell. The signals that induce AID and BCL-6 expression by B cells are not entirely defined, but CD40L, IL-4 and IL-21 contribute. Indeed, the combination of CD40L, IL-4 and IL-21 in different ratios seems to be the primary mix of T cell help signals that control B cell proliferation, somatic hypermutation and differentiation. Class-switch recombination can also be induced by instructive signals from TFHcells to B cells. AID is necessary for class-switch recombination, but the specific target of the heavy chain constant region gene recombination depends on additional factors that are selectively activated by different cytokines, which predominantly, but not exclusively, come from CD4+ T cells. Human IgM to IgG class-switch recombination is most efficiently induced by IL-21, whereas IgE recombination is induced by a high IL-4 to IL-21 ratio.
B cell help crucially depends on cell contact, probably because of a mixture of cell-surface co-stimulatory ligand interactions and directional cytokine production during cognate interactions. Therefore, adhesion molecules expressed by TFHcells and B cells are necessary components of T cell help to B cells, as they regulate the overall duration of the ‘pas de deux’. The most dramatic example of this requirement is SAP, which is described above. SLAM-associated protein (SAP; also known as SH2D1A)binds to the intracellular domains of SLAM family surface receptors, which are involved in cell–cell adhesion. In the absence of SAP, the duration of B cell–T cell adhesion is short and inadequate for the TFHcell to provide sufficient help signals to the B cell. This leads to a general defect in SAP-dependent T cell help to B cells and thus a loss of antigen-specific B cell proliferation and survival, as well as a complete loss of germinal centres and of most memory B cells and long-lived plasma cells.
Finally, chemoattraction is another component of T cell help to B cells. CXC-chemokine ligand 13 (CXCL13) is the ligand for CXCR5 and human germinal centre TFH cells constitutively secrete copious quantities of CXCL13, which probably recruits B cells to colocalize with the TFH cells and to facilitate confinement of the B cells to the germinal centre. Notably, CXCL13 signalling via CXCR5 also modifies B cell adhesion and lymphotoxin synthesis, which shows that CXCL13 also has cytokine-type functions. Thus, chemoattraction is another form of T cell help to B cells.
Therefore, it is conceivable that impaired T cell activation leads to impaired B cell activation and antibody production (reviewed by Crotty (Crotty, 2015)).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent. Again, age-dependent difference in IL-1 signaling is not known.
The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).
These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.
Crotty, S., 2015. A brief history of T cell help to B cells. Nat Rev Immunol 15, 185-189.
Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.