# Loss of TRAF3 in aging B lymphocytes

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2020 · $193,125

## Abstract

B lymphocytes are the cell of origin in the majority of hematologic malignancies, and most human B cell
cancers occur in individuals > 60 years of age. This age group also displays a greater propensity for various
types of immune dysfunction, including both suboptimal immune responses, as well as chronic inflammation.
Understanding how chronic immune-activating signals in aging lymphocytes contribute to both compromised
immunity and increased risk of immune-cell malignancies is critical to developing effective strategies for
interventions to increase `healthspan' of the growing population of humans of older ages. The proposed project
is based upon the recent observation that the signaling adapter protein TNF receptor associated factor 3
(TRAF3) is reduced in protein amounts, but not mRNA, specifically in B (but not T) lymphocytes from older-
aged normal humans and laboratory mice. TRAF3 serves as an important inhibitor of normal B cell
homeostatic survival, as well as a B cell tumor suppressor, so this finding has important biological implications.
The long-term goal of the work of which this exploratory project forms a part is to understand how TRAF3
regulates the function of B and T lymphocytes. The objective of this application is to determine how
posttranslational mechanisms reduce TRAF3 protein in aging B, but not T lymphocytes, and identify which
molecular pathways are crucial to this TRAF3 loss in B cells. The proposed experiments will address two
major working hypotheses, via two Specific Aims. Aim 1 will determine the relationship between TRAF3
protein levels with phenotypic and functional characteristics of B lymphocytes. The working hypothesis to be
tested in Aim 1 is that reduced TRAF3 protein will result in abnormal B cell survival and activation, via
disruption of multiple TRAF3-regulated pathways. Aim 2 will define the age-relevant molecular mechanisms
regulating TRAF3 protein levels in lymphocytes, testing the working hypothesis that chronic inflammatory or
activation signals that increase with the aging process mediate post-translational modification and degradation
of lymphocyte TRAF3 protein in both the cytoplasm and nucleus, altering multiple signaling pathways. Aim 2
will also address why TRAF3 is NOT degraded by TRAF3-associating receptors in T lymphocytes, which may
provide valuable information in designing strategies to prevent B cell aging-related TRAF3 loss. It is expected
that completion of this exploratory project will determine how TRAF3 proteins levels are reduced in aging
lymphocytes, and how reduced TRAF3 impacts the biology and function of B cells. These findings can provide
valuable information to guide interventions that both enhance the immune health of older individuals, as well as
inform therapeutic decisions in treating B cell cancers.

## Key facts

- **NIH application ID:** 9869240
- **Project number:** 1R21AG065532-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** GAIL A. BISHOP
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,125
- **Award type:** 1
- **Project period:** 2020-03-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869240

## Citation

> US National Institutes of Health, RePORTER application 9869240, Loss of TRAF3 in aging B lymphocytes (1R21AG065532-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9869240. Licensed CC0.

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