ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1935

Regulation of T Follicular Helper Cells in Systemic Lupus Erythematosus By E3 Ubiquitin Ligase Cbl-b

William Willis1, Yun Xiao2, Nicholas A. Young1, Wael N. Jarjour1 and Jian Zhang2, 1Immunology and Rheumatology, The Ohio State University Wexner Medical Center, Columbus, OH, 2Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords:

Session Information

Date: Monday, November 9, 2015

Title: T cell Biology and Targets in Autoimmune Disease Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Activation of polyclonal CD4+
T cells and B cells is a hallmark of human and murine lupus,
which suggests a global defect in the maintenance of T and B cell
tolerance. Recent studies unveil a central role of T follicular helper (Tfh)
cells that is critical in providing help to B cells in the overproduction of
pathogenic auto-antibodies and tissue damage in lupus. However, how Tfh cells are deregulated in lupus in mice and humans is currently unknown. The E3
ubiquitin ligase Cbl-b plays a crucial role in T cell activation, tolerance
induction, and Th2 cell differentiation. Cbl-b polymorphisms are linked to
human lupus, and furthermore, Cbl-b expression has been shown to be reduced in
human lupus T cells. However, the role of Cbl-b in lupus pathogenesis is still poorly
defined. In this study,
we test the hypothesis that Cbl-b targets Bcl6, the master transcriptional
regulator for Tfh cell development, for ubiquitination and degradation in mice.

Methods: We introduced Cbl-b
deficiency or a point mutation within RING finger domain of Cbl-b, into lpr mice (carrying a mutation in Fas gene) on
a C57BL/6 background
(B6-lpr.Cblb-/- and B6-lpr.CblbC373A, respectively). To test the feasibility of silencing Cblb in human
T cells, peripheral CD4+ T cells isolated from peripheral blood mononuclear
cells (PBMC) of healthy human donors were transfected with siRNA targeting Cbl-b
using liposomal or nucleofection-based methods.

Results: B6-lpr.Cblb-/- and B6-lpr.CblbC373A mice displayed an exacerbated
and severe lupus-like syndrome. This
was
associated
with expanded
Tfh cells, GC B cells, and plasma cells in the lymph
nodes and spleens
and
heightened
anti-dsDNA
titers in the sera. At molecular level, Cbl-b bound to Bcl-6 upon
Tfh differentiation condition in a Bcl-6 tyrosine-phosphorylation dependent
manner. Furthermore, Bcl-6 ubiquitination and
degradation was abrogated in T cells lacking Cbl-b. Consistent with this data,
Tfh from SLE patients express lower levels of Cbl-b compared to those from
healthy donors.

Conclusion: Our results suggest that that Cbl-b may be the E3
ubiquitin ligase that targets Bcl-6 for degradation. Because both B6-lpr
and human lupus T cells express significantly less Cbl-b, deregulated Cbl-b
expression in human and murine lupus may be a driver of heightened Tfh and GC B
cells causing overproduction of pathogenic auto-antibodies. 

 

 

Disclosure: W. Willis, None; Y. Xiao, None; N. A. Young, None; W. N. Jarjour, None; J. Zhang, None.

To cite this abstract in AMA style:

Willis W, Xiao Y, Young NA, Jarjour WN, Zhang J. Regulation of T Follicular Helper Cells in Systemic Lupus Erythematosus By E3 Ubiquitin Ligase Cbl-b [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/regulation-of-t-follicular-helper-cells-in-systemic-lupus-erythematosus-by-e3-ubiquitin-ligase-cbl-b/. Accessed .

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