Project Summary
Sj¿gren’s syndrome (SjS) is an autoimmune disease affecting the oral and systemic health of 4 million
Americans. Characterized by chronic inflammation and dysfunction of exocrine glands, SS causes dry mouth,
dry eyes and various systemic health problems, with no cure or effective biological therapy available. The
objective of this R01 project is to elucidate the negative impact of IL-7 and Th1 cytokines on Treg function in SjS
disease, and to test if enhancing TCF1 and Tim-3 in Tregs can improve and enhance their suppressor function,
resistance to IL-7/Th1 cytokines, and the ability to ameliorate SjS. Tregs in SjS-prone non-obese diabetic mice
are functionally impaired. Pro-inflammatory cytokines, including Th1 cytokines IFN¿ and IL-12, can impair the
function and stability of Tregs to promote autoimmune inflammation. Our preliminary studies yielded important
evidence for the formation of our central hypothesis that IL-7 and Th1 cytokines contribute to aberrant Treg
function in SjS conditions, in part by downregulation of TCF1 and Tim-3, and that enhancing the
expression/activity of TCF1 and Tim-3 may improve and boost the immunosuppressive function, stability and
SjS-attenuating ability of these Tregs. In Aim 1, we will determine if forced expression of TCF1 in Tregs with
lentiviral gene expression vectors can improve/enhance their immunosuppressive function, stability under
inflammatory conditions, and ability to ameliorate SjS. In vitro Treg functional assays and in vivo Treg transfer
to SjS mouse model will be employed. In Aim 2, we will determine if enhancing Tim-3 activity or expression in
Tregs can improve and boost their immune-regulatory and SjS-attenuating function. We will enhance Tim-3
activation or expression using several approaches, including in vivo injection of Tim-3 ligand, in vitro stimulation
of Tregs with Tim-3 ligand, and force-expressing Tim-3 in Tregs using lentiviral vectors. We will test if enhancing
Tim-3 expression/activation can improve/boost the immunosuppressive function of normal and SjS-affected
mouse and human Tregs. In Aim 3, we will comprehensively define the transcriptomic changes in mouse and
human Tregs associated with SjS and induced by IL-7 and Th1 cytokines with high throughput NGS RNA-
sequencing, which will identify new molecular players and pathways underlying the defective Treg function in
SjS and induced by IL-7 and Th1 cytokines. Completion of this project will address a critical knowledge gap and
advance both basic understanding and translational modulation of Treg function and stability, which could lead
to development of Treg-based strategies for ameliorating SjS and various other autoimmune diseases in future.
