Cell-intrinsic genetic regulation of peripheral memory-phenotype T cell frequencies

Abstract

4344 Gene-environment interplay in immune phenotypes has been extensively studied using steady-45 state cellular immune profiles (1-3), functional immune responses (2,(4)(5)(6)(7)(8), post-vaccination 46 responses (9,10) and V,D and J usage biases in naïve and memory T and B cell compartments 47 (11). Some of these studies have identified genomic correlates associated with specific steady-48 state immune phenotypes (2) and vaccine responses (12). However, there are conflicting findings 49 regarding the relative importance of genetic versus environmental factors in regulation of 50 immune phenotype (1,2,13,14), warranting further investigations at the population-level in 51 humans and mechanistic studies in mice on regulation of individual immune phenotypes. 52 53 Memory subsets in T and B lymphocytes are immune populations that are generated in response 54 to past immunogen exposure. Immunological memory, providing long-term persistence of 55 antigen-experienced cells contributing to rapid and robust responses following re-exposure (15), 56 is likely to have evolved in an ecosystem where environmental challenges including repeated 57 infections would be the norm (16) and the persistence of long-lasting antigen-specific cells 58 generated during immune responses would confer survival advantage (17). However, it is 59 possible that larger memory lymphocyte pool sizes may carry costs such as restriction of space 60 for the more repertoire-diverse naive T cell compartment (18), attrition of pre-existing memory 61 (19), and other bioenergetic costs (20). Such selection may well result in 'optimum' sizes of 62 memory lymphocyte pools (21), and these pool sizes could show population diversity, depending 63 on the diversity of pathogens in the ecosystem and their exposure rates (22). Diversity in pool 64 sizes of memory lymphocytes in a population could thus be determined by a combination of 65 genetic variability and diversity of environmental exposures. 66 4 67 A number of mechanisms can be envisaged regulating the pool size of the memory T cell 68 compartment, including cumulative life-time antigen-exposure and re-exposure, antigenic 69 persistence, degree of expansion, cell survival, attrition and niche-space availability (21,23-26). 70 Immune cells occupy a limited niche space in lymphoid organs (27) or in the periphery (28). This 71 niche size could be a function of size and/or structure of supporting lymphoid tissue architecture 72 (29), along with intrinsic properties of cells occupying the niche. Similar determinants could 73 affect steady state levels of transient cell populations such as immediate-effector T cells (30) and 74 plasmablasts, but their steady state levels would be expected to fluctuate more with short-term 75 environmental changes. 7677 On this background, we have explored the possibility of gene-environment interplay affecting the 78 steady state pool sizes of lymphocytes post-activation. We have used peripheral blood leucocyte 79 immunophenotyping in serial bleeds from healthy young adult hum...