Muljo/Bassing

Project Title

Elucidating the fetal lymphopoiesis program

NIH Mentor

Stefan A. Muljo

Penn Mentor

Craig H. Bassing

Project Details

The ability to generate immune systems that discriminate between self and foreign antigens is vital for the life, health, and reproduction of mammals. Starting in utero, mammals develop several distinct lymphocyte lineages. Among the first waves of cells that arise from fetal lymphoid organs, innate-like lymphocytes such as B-1 and NKT cells express semi-invariant antigen receptors. This is in part because during their development, they do not employ terminal deoxynucleotidyl transferase (TdT) which can catalyze non-templated addition of nucleotides during V(D)J recombination to increase junctional diversity. Furthermore, early in life, the chromatin accessibility and structure of developing progenitor B cells derived from fetal liver is likely to be different than their counterparts in adult bone marrow but this has not been investigated. Similarly, in the fetal and newborn thymus, there are highly programmed waves of T cell receptor gamma rearrangements and this is distinct from the programs observed later in adult thymus. However, the underlying molecular programs that orchestrate these unique processes have not been thoroughly explored. While in adults, conventional lymphocytes express highly diverse antigen receptors assembled from recombination of the entire repertoire of germline variable (V) gene segments with diversity (D) and joining (J) gene segments. The molecular details of V(D)J recombination during adult lymphopoiesis has been extensively studied in contrast to what happens early in life. Developing B and T cells share developmental strategies that include mono-allelic gene recombination and feedback mechanisms, which link antigen receptor protein expression from functional rearrangements to further developmental progression or negative selection of auto-reactive cells. However, the genetic, epigenetic, and biochemical mechanisms governing these facets of B and T cell differentiation during early life remain largely unknown. For example, B-1 cells are enigmatic since they also confer some risks to the host as evidenced by generation of auto-reactive B cell receptors that can lead to autoimmunity (eg. antiphospholipid syndrome) and lymphoid malignancies such as a subset of chronic lymphocytic leukemia (CLL). Thus, a major aim of this collaborative project is to compare and contrast the fetal programs of lymphocyte development to their adult counterparts. We believe that these avenues of investigation will lead to discoveries that raise important novel questions about how immune systems are formed, and broad-ranging implications for basic immunology research and the screening, diagnosis, and treatment of human immunological and infectious diseases.