Monday, May 19, 2025
5/19/2025
Elucidating a novel respiratory-mammary axis of T cell immunity - Breastfeeding is associated with immunological benefits that persist beyond infancy, including reduced risk of respiratory infection. While these benefits are often attributed to immunoglobulins and antimicrobial compounds, human milk is also rich in T cells whose function is unknown. A central goal of my research career is to elucidate the protective function of breastmilk T cells against infant respiratory infection. To this end, I propose to investigate the respiratory-mammary axis of cellular immunity and its role in the establishment, retention, and response of tissue resident memory T cells (TRM) in the lactating breast. I hypothesize that i) maternal exposure to respiratory infections results in priming of T cell populations that go on to seed TRM in both the breast and the respiratory tract and ii) antigen exposure via saliva of the nursing infant drives persistence of TRM in the lactating breast. I will use samples from a cohort of mother infant pairs, which includes breastmilk cells (BMC), nasal mucosal cells (NMC), and peripheral blood mononuclear cells (PBMC). In Aim 1, I will investigate whether T cells resident to the upper respiratory tract and lactating breast are derived from a shared cellular population by defining the transcriptional and clonal overlap of T cells from BMC and NMC using single cell RNA sequencing with paired T cell receptor (TCR)αβ sequencing. In Aim 2, I will evaluate the contribution of infant respiratory infection and coinciding maternal and infant respiratory infection on the frequency and functional state of breastmilk T cell subsets. To do this, I will enroll mother-infant pairs seeking care at Seattle Children’s Urgent Care clinics with PCR-confirmed infant SARS-CoV-2 or influenza A. BMC from acute and convalescent timepoints will be evaluated by high-parameter flow cytometry for T cell immunophenotyping. In Aim 3, I will interrogate breastmilk antigen-specific TRM responses in the setting of maternal and infant respiratory syncytial virus (RSV) infection. I will enroll mother-breastfed infant pairs who present to urgent care with PCR-confirmed infant RSV infection in which i) both the mother and infant are infected with RSV or ii) only the infant is infected, I will stimulate maternal BMC from these pairs (along with those from healthy controls) with an RSV peptide pool and assess the frequency and phenotype of T cells expressing activation-induced markers (AIM) using flow cytometry. These studies will elucidate the establishment, retention, and response of TRM in the lactating breast, with relevance to future work to discern how these cells may protect against infant respiratory infection. The proposed work will take place at Seattle Children’s Research Institute under the co-mentorship of Dr. Whitney Harrington and Dr. Alexis Kaushansky. I have additionally recruited a scientific advisory committee who will support my success in achieving the proposed aims; my short-term objectives of gaining skill/expertise in mucosal T cell biology, human study design, and computational biology; and my transition to an independent faculty position. In short, this award will empower me to achieve my long-term goal of leading a research program focused on infection and immunity during pregnancy, post-partum, and infancy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).