# Intrinsic and Extrinsic factors regulating competition for active TGFb promote skin memory CD8 T cell fitness

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $550,909

## Abstract

Abstract
Resident memory T cells (Trm) are a recently appreciated subset of memory T cells that
maintain long-term residence in barrier tissues. Unlike central memory T cells that reside in the
lymph node and spleen, Trm are prepositioned at the site of a prior infection/inflammation where
they provide a rapid immune response to subsequent challenges. In the skin, CD8+ Trm reside
primarily in the epidermis and provide protective memory responses to herpes simplex and
vaccinia virus infections that exceeds the protection provided by central memory T cells. In
addition, epidermal Trm provide immune-surveillance against melanoma and are likely
pathogenic in many autoimmune diseases. Understanding the basic biology of these cells is
central to efforts to maximize barrier host defense and treat numerous diseases. In past cycles
of the grant we showed that persistence of CD8+ Trm in the epidermis requires autocrine TGFβ
that must be transactivated by avβ6 or avβ8 expressed by keratinocytes. We also found that
partial blockade of avβ6 and avβ8 by mAb or small molecule inhibition could eliminate
epidermal Trm. Importantly, only Trm that had not re-encountered cognate antigen in the skin
were depleted. In contrast, Trm that re-encountered cognate antigen in the skin were able to
persist when levels of active TGFβ were artificially suppressed. Thus, a second encounter with
cognate antigen in the skin during development renders Trm less dependent on active TGFβ
and represents a mechanism to preferentially deplete ‘bystander’ Trm during subsequent
rounds of infection/inflammation. Moreover, TCR ligation during development in the skin
promotes Trm ‘fitness’ and is an unappreciated obligate final step in the development of robust
epidermal Trm. In Aim 1, we will test the hypothesis that TCR-induced alteration of the
chromatin state is a key determinant of Trm ‘fitness’. We hypothesize that the niche size is
flexible and that expression levels of avβ6 by keratinocytes is a key T cell-extrinsic factor
determining its size. In Aim 2, we will develop mice with doxycycline controllable Itgb6
expression and test our hypothesis by directly manipulating αvβ6 expression at varying times
following Trm development. Finally, we hypothesize that both T cell ‘fitness’ and TGFβ
transactivation by the niche participate to shape antigen-specific CD8+ T cell pools in the
context of chronic antigen. In Aim 3, we will test this hypothesis using a transplantable B16
melanoma model in which T cell ‘fitness’ and stromal TGFβ transactivation will be manipulated.

## Key facts

- **NIH application ID:** 10995025
- **Project number:** 1R01AR083713-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Daniel H Kaplan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,909
- **Award type:** 1
- **Project period:** 2024-07-20 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995025

## Citation

> US National Institutes of Health, RePORTER application 10995025, Intrinsic and Extrinsic factors regulating competition for active TGFb promote skin memory CD8 T cell fitness (1R01AR083713-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10995025. Licensed CC0.

---

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