Principal Investigator: Brian Rudd

DESCRIPTION (provided by applicant): 

Malnutrition is a serious public health issue facing women and children and is linked to increased morbidity and mortality worldwide. Both developed and developing countries have reported a high prevalence of vitamin D (VITD) deficiency in women of child bearing age, with adverse consequences on bone and immune health for the fetus and growing infants. While the American Academy of Pediatrics (AAP) recommends that breastfed infants receive daily supplements of VITD shortly after birth, we still lack critical information regarding the relationship between maternal VITD levels and the development and function of CD8+ T cells in their offspring. Previous work performed in adult animals has highlighted a role for VITD in the generation of memory CD8+ T cells following infection. However, the underlying basis for how VITD alters the balance of effector and memory CD8+ T cell differentiation remains an open question. Our theory is that VITD alters the ability of neonatal CD8+ T cells to transition into long-lived memory cells by modulating the expression of let-7. This theory is supported by the following evidence: (i) let-7 contains a VITD response element (VDRE) in its promoter region; (ii) numerous studies have shown that VITD drives the expression of let-7 in a wide variety of cell types(2-5); and (iii) the regulation of let-7 by VITD appears to be a highly conserved pathway found in Drosophila, nematodes, and mammals. Based on these studies and our own preliminary data, we believe that the let-7/Lin28b axis serves as a VITD-inducible switch, promoting the development of memory CD8+ T cells when VITD levels are abundant or the generation of effector CD8+ T cells when VITD levels are insufficient. In this supplement, we will apply rigorous analysis of the CD8+ T cell response in neonatal mice raised on different amounts of VITD and test the hypothesis that VITD promotes the generation of memory CD8+ T cells by upregulating expression of let-7, which limits proliferation and terminal differentiation of effector cells. The aims of the grant are as follows: SA1 Understand how regulation of let-7 by VITD changes the ability of neonatal CD8+ T cells to respond to infection. SA2 Elucidate the let-7-regulated metabolic programs that are altered by VITD in neonatal CD8+ T cells. Upon completion of this work, we will have obtained a complete mechanistic understanding of how VITD influences the T cell response after activation. Our focus on the relationship between VITD and let-7 will allow us to manipulate the number and type of memory CD8+ T cells that are generated in specific ways. This is a novel and targeted approach to enhancing memory T cell development in early life.