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Stochasticity Open Seminar June 13, 2017, 14:00

Open Seminars of the Research Group on


Stochasticity and Control in the Dynamics and Diversity of Immune Repertories: an Example of Multi-Cellular Co-Operation


Tuesday, June 13, 2017, 14:00

at the Israel Institute for Advanced Studies, Room 128




The origins of cellular selection in adaptive immunity


Martin Flajnik (University of Maryland)


Often overlooked in the origins of adaptive immunity, secondary lymphoid organs (SLO) play a major role in the generation of high affinity immune responses. The spleen is the oldest SLO, first appearing in the jawed vertebrates (gnathostomes, the oldest living group the cartilaginous fish), having a segregation of B and T cell zones. We have shown recently that there is a single population of antigen presenting cells (APC) in amphibians, which can present antigen to both B and T cells (the so-called “XL cell”). After immunization with a foreign antigen, these APC were shown to display antigen on their surface, probably in the form of immune complexes and covalently-bound complement, and they migrate into B cell zones in a T cell-dependent manner. XL cells are of a hematopoietic origin and bear high levels of MHC class II molecules, which also have them poised to present antigens to T cells. We propose that these APC perform a ‘double-duty,’ presenting antigen to both T cells and B cells in the course of a response. A model will be presented in which antigen is first presented to T cells, and then activated T cells license the same APC to present cell-bound antigen to B cells. A large leap forward in evolution, therefore, occurred in mammals with the appearance of follicular dendritic cells (FDC), non-hematopoietically derived APC that reside perpetually in B cell follicles, orchestrating the maintenance of the B cell follicle as well as the formation of germinal centers. Thus, although somatic hypermutation and antigen selection arose at the origins of adaptive immunity, the division of labor between two types of APC, conventional DC and FDC, provided another tier to the ability of the immune system to mutate and select high affinity B cell clones. Jawless fish, which have an adaptive immune system based on a convergent set of antigen receptors (the VLR), have T and B cells as well, but no known SLO. It is a challenge to understand how these vertebrates are able to make efficient immune responses.



Related Research Questions


  1. The tumor necrosis factor (TNF)-related cytokines lymphotoxins (LT) are crucial for the formation of FDC and germinal centers. Cold-blooded vertebrates lacking FDC nevertheless have these cytokines (encoded within the MHC). What might be the primordial functions of LT in these animals?
  2. In the absence of germinal centers, some ectothermic vertebrates are capable of selection of high affinity antibodies with marks of positive selection. How might this be achieved, i.e. what testable hypothesis could we put forward?
  3. Even when SLO are absent, in the case of jawless fish, B cells seem to undergo somatic mutation and some level of selection. What can explain this phenomenon?


Suggested Reading


Emergence and Evolution of Secondary Lymphoid Organs

Harold R. Neely and Martin F. Flajnik

Annual Review of Cell and Developmental Biology Vol. 32:693-711 (Volume publication date October 2016)



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