Abstract
Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR)β sequences of Tfh located in GCs of both contralateral draining lymph nodes. We found that over 90% of the dominant GC-Tfh clonotypes were shared in both lymph nodes but only transiently. The initially dominant Tfh clonotypes especially declined after establishment of chronic disease while GC reaction and autoimmune disease continued. Our data demonstrates a dynamic behavior of Tfh clonotypes under autoimmune conditions and emphasizes the importance of the time point for distinguishing auto-Ag-specific Tfh clonotypes from potential bystander activated ones.
Highlights
Germinal centers (GCs) are transient organized microstructures within secondary lymphoid tissues, which support the development of high-affinity antibodies by B cells
germinal center (GC) reactions occur in both draining lymph nodes
To evaluate T cell receptor (TCR) sequences of GC-Tfh in separate lymph nodes, we used the autoimmune model for the autoantibody-induced skin blistering disease epidermolysis bullosa acquisita (Hammers et al, 2011; Sitaru et al, 2006; Figure 1a and Figure 1—figure supplement 1)
Summary
Germinal centers (GCs) are transient organized microstructures within secondary lymphoid tissues, which support the development of high-affinity antibodies by B cells. The differentiation into Tfh initiates in T cell zones of lymphoid organs before GC formation starts After their interaction with B cells at the T-B border, Tfh locate within GC (GC-Tfh) and regulate the survival of proliferating GC-B cells, which compete for antigen (Ag) and for signals from GC-Tfh to undergo further somatic hypermutation and to mature into high-affinity-antibody-producing plasma cells and memory B cells (Crotty, 2019; Qi, 2016). GC-Tfh are central players in the regulation of humoral immune responses Both (i) their differentiation into GCTfh and (ii) their survival and clonal expansion within GCs are constantly driven by competition for Ag contacts (Baumjohann et al, 2013; Fazilleau et al, 2009; Hwang et al, 2015; Knowlden and Sant, 2016; Tubo et al, 2013; Merkenschlager et al, 2021)
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