# CTLA4 expressed in B-1a regulates B-1a immune function

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $404,011

## Abstract

Modern vaccine and other immune strategies take for granted that the mechanisms that define the B cell
antibody repertoire and underlie B cell primary and memory responses are relatively well understood. However,
our recent studies underscore an important gap in this understanding. We have plays a key role in regulating B-
1a autoantibody production. To explore the mechanisms underlying this CTLA4-mediated B-1a regulation, we
generated conditional knockout mice (CKO) in which CTLA4 is specifically deleted in B cells but remains normal
in T cells. Our preliminary studies show that ablation of CTLA4 in B cells results in a) increased B-1a expansion;
b) spontaneous formation of germinal centers (GC) in spleen; and c) a striking increase in hyper-mutated class-
switched B cells whose origins (B-1a or other B) remain elusive. As a result, serum IgG and IgE are remarkably
elevated in CTLA4 B cell CKO mice.
 Intriguingly, we also find that T follicular helper cells (CXCR5+PD-1hiBcl6+), a specialized CD4 T effector
subset that provides essential help for GC B cells, is spontaneously induced in CTLA4 B cell CKO mice.
Consistent with this finding, we further find that like typical GC responses induced by immunizing with foreign
antigens, the spontaneous GC responses in CTLA4 B cell CKO depend on CD4 T cells and CD40 signaling.
Finally, we find that autoreactive IgG and IgE, e.g., anti-ANA and anti-dsDNA, are generated in CTLA4 B cell
CKO mice and that these mutant mice develop autoimmune pathology as animals age. Taken all together, these
findings strongly argue that, as in T cells, CTLA4 also acts as a key checkpoint regulator for B-1a function.
 In studies here, we focus on the cellular and molecular mechanism(s) that mediate CTLA4 regulation of B-
1a activation, thereby controlling B-1a IgM and IgG natural antibody production and their other immune functions.
Our findings potentially offer insights into the mechanisms operating in antibody-mediated autoimmune diseases.
Beyond autoantibody production, our studies can be expected to elucidate previously unrecognized roles that B-
1a cells play in maintaining immune homeostasis and self-tolerance. Of practical interest, studies here may offer
insights into the mechanism underlying the pathologic autoimmune responses associated with the otherwise
promising “CTLA4 blockade” immune therapy for advanced human neoplasms.

## Key facts

- **NIH application ID:** 9841724
- **Project number:** 5R01AI129939-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Leonore A. Herzenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,011
- **Award type:** 5
- **Project period:** 2018-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841724

## Citation

> US National Institutes of Health, RePORTER application 9841724, CTLA4 expressed in B-1a regulates B-1a immune function (5R01AI129939-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841724. Licensed CC0.

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