# CD1d-Restricted NKT Cells Promote Central Memory CD8+ T Cell Formation via an IL-15-pSTAT5-Eomes Axis in a Pathogen-Exposed Environment

## TL;DR

This study shows that CD1d-restricted NKT cells help form memory T cells in a microbe-rich environment through an IL-15 signaling pathway.

## Contribution

The study identifies a novel role of CD1d-restricted NKT cells in promoting central memory T cell formation via an IL-15-pSTAT5-Eomes axis in pathogen-exposed settings.

## Key findings

- CD1d-restricted NKT cells regulate central memory T cell formation in a microbe-rich environment.
- NKT cells enhance IL-15Rα expression on CD4+ T cells, promoting IL-15 trans-presentation and activating the IL-15/pSTAT5/Eomes axis.
- Microbiota-experienced niches shape immune memory through NKT cell-dependent mechanisms.

## Abstract

The generation of memory CD8+ T cells is essential for establishing protective T cell immunity against pathogens and cancers. However, the cellular and molecular mechanisms underlying memory CD8+ T cell formation remain incompletely understood. Reliance on specific pathogen-free (SPF) models, characterized by restricted microbial exposure, may limit our understanding of physiologically relevant immune memory development. This study reveals that CD1d-restricted NKT cells regulate central memory T cell (TCM) generation exclusively in a microbe-rich (“dirty”) environment. Under non-SPF housing, CD1d+/− and Ja18+/− mice exhibited enhanced TCM formation compared to NKT-deficient controls (CD1d−/−/Ja18−/−), demonstrating that microbial experience is required for NKT-mediated TCM regulation. Mechanistically, CD1d-restricted NKT cells increased IL-15Rα expression on CD4+ T cells in CD1d+/− mice, potentiating IL-15 trans-presentation and thereby activating the IL-15/pSTAT5/Eomes axis critical for TCM maintenance. Functional validation through adoptive transfer of CFSE-labeled OT-1 memory cells revealed an NKT cell-dependent survival advantage in CD1d+/− hosts. This provides direct evidence that microbiota-experienced niches shape immune memory. Collectively, these findings establish CD1d-restricted NKT cells as physiological regulators of TCM generation and suggest their potential utility as vaccine adjuvants to enhance protective immunity.