Erythroid cell modulation of T cell function

University Of Vermont & St Agric College, Burlington VT

Investigators

Abstract

? DESCRIPTION (provided by applicant): There is critical need for enhanced understanding of the developing immune system in order to increase the health of children and the adults they become. Infectious diseases more harshly affect the newly born, the prematurely born, and the young under the age of five. Young children can be affected by inappropriate inflammatory or adaptive immune responses to environmental antigens and this may predispose them to allergic or autoimmune disease. Finally, the altered development of the early immune system plays a role in childhood cancer. Recent thinking is that the neonatal immune system is a sum of interactions between `fetal' and `adult' components, however, little is known about how these `systems' interact, transition, or affect overall immunity in neonates. We have studied the mouse immune system between 1-3 weeks of life, as many aspects model the immune system of mid-late gestational and newborn humans. We have observed striking changes during this time frame. For example, before T cells fully populate the spleen, a unique erythrocyte lineage (EL) cell expands to a peak on days 6 of life, is the dominant population in the spleen for several days and then contracts to near adult levels by day 21 of life. The fall in EL is concomitant with rise in spleen T cells. Co- culture between neonatal EL and adult CD4 T cells led to increased EL production of IL-6 and in turn was associated with decreased ¿IFN and increased IL-4 production by CD4 T cells. These observations and existing evidence suggesting that both EL and T cells respond to the growth factor IL-7 lead us to the novel overall hypothesis that in vivo expansion and contraction of EL as well as expansion of T cells in the neonatal spleen is regulated by competition for IL-7 and that activation of EL in this context increases EL-produced IL-6 which in turn directly supports Th-2 differentiation in vivo during this period of neonatal life. The work proposed in this R21 application takes advantage of unique genetically manipulated mice, the experience of an expert in the role of IL-6 in the regulation of immune responses and a laboratory experienced in both the study of T cell homeostasis and maternal and neonatal immunity. The results are expected to inform development of methods to diagnose immune dysfunction in preterm and term human infants, and guide investigation of methods to enhance protective and modulate inappropriate immunity in the neonatal period.