# Brain T cell interactions in microbial experienced mice

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2024 · $233,250

## Abstract

T cells in the brain have long been associated with pathogenic outcomes, with the healthy brain considered an
immune privileged organ. This concept has recently been overturned with the description of meningeal
lymphatics, roles for immune cells in normal brain homeostasis, and detection of T cells in the brains of healthy
subjects and in aging subjects with neurological disease. Why these T cells are in the healthy brain and what
role they play in this critical tissue remain major knowledge gaps. Due to their abnormally hygenic housing
conditions, young adult SPF mice display peripheral immune systems that resemble infant cord blood. In
contrast, signatures of repeated microbial exposure are already evident in children and young adult humans
and these signatures intensify with age. Specific to this proposal, young adult SPF mice, which are the
subjects in many if not most animal models of neuroscience research, have low numbers of T cells in their
brains at homeostasis. Several models have been implemented to “normalize” the peripheral immune system
of inbred SPF mice to better mimic humans. One informative approach, to generate such “dirty mice” leverages
the co-housing (CoH) of SPF mice with pathogen-infested “pet store” mice to permit natural transfer of mouse
pathogens. Alternatively, repeated exposure of SPF mice to known laboratory pathogens (Specific Pathogen
Exposed, SPExp mice) has emerged as a tractable approach that can be used at lower biocontainment than
the CoH approach. Studies with these models have largely focused on understanding how “normalization” of
the immune system influences peripheral immune responses to infection or tumors within lymphoid organs and
barrier tissues. Thus, the impact of repeated microbial exposure on the generation of brain-surveilling T cells is
currently unknown. Our preliminary studies reveal that not only does repeated microbial exposure normalize
the peripheral immune system, it also results in substantial and specific increases in memory CD4 and CD8 T
cell numbers in the brain. In parallel, our preliminary data show here that brain-residing T cells interact with
other immune cells in the CNS, including CD11c+ dendritic cells (DCs), that perform essential functions during
brain homeostasis and in response to brain trauma, infections, tumors, and neurodegeneration. Due to the
heavy reliance on SPF mice for studies of brain function, the consequences having “normalized” populations of
brain-residing memory T cells during homeostasis or neurological disease remain unknown. Our long-term
goal is to exploit models of repeated microbial exposure to “normalize” the immune system and understand the
roles of brain-residing memory T cells in shaping brain function and neuroimmune responses. Specific Aim 1.
Determine how “normalized” numbers of brain-residing CD8 and CD4 T cells impact the functional
status and cellular interactions of brain microglia and CD11c+ DCs at homeostasis. 1.1. Determine the
epigeneti...

## Key facts

- **NIH application ID:** 10948778
- **Project number:** 1R21AI185067-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** John T Harty
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2024-06-04 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948778

## Citation

> US National Institutes of Health, RePORTER application 10948778, Brain T cell interactions in microbial experienced mice (1R21AI185067-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10948778. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*