How genes are selected to create diverse immune cell receptors

 How genes are selected to create diverse immune cell receptors

Use of a new technique researchers to take an in-depth look at the gene shuffling process that is responsible for our body's ability to recognize a vast range of foreign agents such as disease-causing microorganisms (pathogens). Failure in this process lies at the heart of a variety of immunodeficiency diseases and is also relevant to the decline in immune function observed with age.

To ensure this diversity, antigen receptors, the cellular receptors that recognize the presence of pathogens, are assembled from gene segments picked from a wider selection. Every antigen reception is made of a V (variable), D (diversity) and J (joining) region but there are several of each of these regions to choose from. In mice for example, there are 4 J genes, 10 D genes and 195 V genes in the immunoglobulin heavy chain antigen receptor. Mix and matching the regions allows our body to create an enormous range of receptors ensuring that our immune surveillance is equipped to recognize and respond to most pathogens.

How the different V, D and J segments are selected has remained a key question for immunology researchers. In research just published in Cell Reports, the researchers used the technique, called VDJ-seq, to look particularly at the frequency of use of the 195 V genes in an immune cell type from mice. By using cutting-edge machine learning techniques to integrate this information and the data from genetic and epigenetic analyses, they uncovered the regulatory rules explaining why particular V segments were used or unused.

Authors identify combinatorial patterns of epigenetic features that associate with active VH gene recombination. These features localize downstream of VH genes and are excised by recombination, revealing a class of cis-regulatory element that governs recombination, distinct from expression.

Researchers detect two mutually exclusive chromatin signatures at these elements, characterized by CTCF/RAD21 and PAX5/IRF4, which segregate with the evolutionary history of associated VH genes. Thus, local chromatin signatures downstream of VH genes provide an essential layer of regulation that determines recombination efficiency.

The co-first author on the paper, said: "The selection of the different gene segments to create a receptor is not random. Our research showed that there is a wide range in frequency with which a particular V gene segment is utilized. This points to the involvement of complex regulatory mechanisms and our findings contribute towards establishing what these are and how they influence the selection." Another co-first author on the paper, added: "Integrating the frequency of selection of different V segments with information on other factors also playing a role in recombination efficiency allowed us to establish the pattern of features that are associated with active V segment usage."

Co-corresponding author, said: "Understanding the VDJ recombination process is important because it is the first determinant of receptor diversity. Having a precise readout of which V, D and J segments are used advances our understanding of the process of recombination and how this is regulated. These finding have implications for immune disorders and aberrant VDJ recombination in cancer."