Rab4A controls the depletion of IL-2 in CD4⁺ T cells via enhanced CD38 expression: Potential involvement in pro-inflammatory skewing in systemic lupus erythematosus

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B761
Abstract ID: 4923

Presenting Author:
Joy S. Park , PhD Candidate at SUNY Upstate Med. Univ.

Abstract:

Rab4A, a small GTPase overexpressed in SLE patient T cells, mediates receptors recycling, and activates mTOR. Increased CD38 expression, mTOR activation, and reduced IL-2 production are implicated in pro-inflammatory T cell development in SLE. We studied the impact of Rab4A on CD38 expression and IL-2 production and the impact of CD38 expression on mTOR activation in CD4⁺ T cells.

We mutated Jurkat cell lines: Rab4A overexpressed (Rab4A⁺⁺) and dominant-negative mutant Rab4A^S27N (Rab4A^DN). CD38 was also KO. We isolated PBMCs from SLE patients (n=21) and healthy controls (n=18).

In Rab4A⁺⁺ cells, CD38 and pSTAT3 increased, while IL-2 and NAD⁺ decreased. CD38 KO in Rab4A⁺⁺ cells increased NAD⁺ and IL-2 and decreased pSTAT3. In CD4⁺ T cells, CD38⁺ vs. CD38^- cells showed increased pAkt1 in SLE patients, and increased p4EBP1 in SLE patients and healthy controls. Rapamycin increased CD38 surface expression and decreased intracellular IL-2 in all Rab4-mutated lines.

Elevated pAkt1 and p4EBP1 in SLE CD38⁺ CD4⁺ T cells align with the CD38/PI3K/Akt/mTOR axis in cancer. Rapamycin reduced IL-2 production and increased CD38 expression, suggesting that CD38 regulates IL-2 independently of mTOR. CD38, an NAD⁺ hydrolase, regulates Sirtuin-1, a NAD⁺-dependent histone deacetylase that suppresses STAT3. Elevated pSTAT3 levels may suppress IL-2 production via FoxO1. Our results suggest Rab4A overexpression may drive decreased IL-2 secretion via increased CD38 expression in SLE.