Project Grant R37AI189855

MAPPING INFANT AND ADULT T CELL IMMUNITY - PROJECT SUMMARY / ABSTRACT THE PRIMING OF CD8+ T CELLS IN THE LYMPH NODE ULTIMATELY DETERMINES THE SUCCESS OF THE HOST RESPONSE TO INTRACELLULAR PATHOGENS. PRIMING DETERMINES WHETHER THE PATHOGEN IS CLEARED BY EFFECTOR T CELLS AND IMMUNITY IS ESTABLISHED BY MEMORY CELLS. DESPITE THE IMPORTANCE OF THIS KEY STEP, OUR UNDERSTANDING OF THE EVENTS THAT OCCUR IN THE LYMPH NODE EARLY AFTER INFECTION IS STILL CONSIDERED A BLACK BOX AND IS LARGELY BASED ON STUDIES PERFORMED IN ADULT ANIMALS. INDEED, THERE IS ALMOST NO INFORMATION AVAILABLE ON HOW THE LYMPH NODES CHANGE FROM BIRTH TO ADULTHOOD. AS A RESULT, WE DO NOT UNDERSTAND HOW T CELLS BECOME ACTIVATED IN THE LYMPH NODE AT DIFFERENT STAGES OF LIFE, AND THE LACK OF SUCH INFORMATION HAS MADE IT DIFFICULT TO DEVELOP NEW STRATEGIES TO ENHANCE IMMUNITY IN EARLY LIFE. USING NEW TECHNOLOGY, WE PLAN TO CONSTRUCT THE FIRST MOLECULAR ATLAS OF T CELL DEVELOPMENT IN LYMPH NODES AND DETERMINE HOW THE CELLULAR INTERACTIONS AND COMMUNICATION NETWORKS CHANGE DURING CD8+ T CELL PRIMING THROUGHOUT CHILDHOOD. OUR HYPOTHESIS IS THAT CD8+ T CELLS MADE IN EARLY LIFE ARE LOCATED IN AN 'INNATE NICHE' NEAR THE SUBCAPSULAR MACROPHAGES AND HELP TO LIMIT TRANSNODAL SPREAD OF PATHOGENS DURING THE PRIMARY RESPONSE, WHEREAS CD8+ T CELLS MADE IN ADULTHOOD ARE FOUND IN AN 'ADAPTIVE NICHE' NEAR THE CENTRAL PARACORTEX AND ARE SUPERIOR AT PROVIDING SYSTEMIC PROTECTION TO SECONDARY INFECTIONS. IN THE FIRST AIM, WE WILL DETERMINE HOW THE SPATIAL ORGANIZATION OF T CELLS CHANGES IN THE LYMPH NODE THROUGHOUT CHILDHOOD. IN THE SECOND AIM, WE WILL EXAMINE HOW THE LYMPH NODE SHAPES THE CD8+ T CELL RESPONSE TO INFECTION IN INFANTS AND ADULTS. IN THE THIRD AIM, WE WILL EVALUATE THE IMPACT OF MICROBIAL EXPOSURE ON THE DEVELOPMENT AND FUNCTION OF LYMPHOID CD8+ T CELLS. THE OBTAINED RESULTS ARE EXPECTED TO PROVIDE THE RESEARCH COMMUNITY WITH A NEW PARADIGM FOR T CELL ACTIVATION AND AN INVALUABLE RESOURCE FOR UNDERSTANDING HOW IMMUNE RESPONSIVENESS CHANGES AT VARIOUS STAGES OF LIFE. THIS NEW ATLAS OF T CELL DEVELOPMENT HAS BROAD IMPLICATIONS FOR THE DESIGN OF MORE PRECISE IMMUNOTHERAPIES AND THE DEVELOPMENT OF MORE EFFECTIVE VACCINES.