Abstract
Crosslinking ligand-engaged cytotoxic T lymphocyte antigen-4 (CTLA-4) to the T cell receptor (TCR) with a bispecific fusion protein (BsB) comprised of a mutant mouse CD80 and lymphocyte activation antigen-3 (LAG-3) has been shown to attenuate TCR signaling and to direct T-cell differentiation toward Foxp3+ regulatory T cells (Tregs) in an allogenic mixed lymphocyte reaction (MLR). Here, we show that antigen-specific Tregs can also be induced in an antigen-specific setting in vitro. Treatment of non-obese diabetic (NOD) female mice between 9–12 weeks of age with a short course of BsB elicited a transient increase of Tregs in the blood and moderately delayed the onset of autoimmune type 1 diabetes (T1D). However, a longer course of treatment (10 weeks) of 4–13 weeks-old female NOD animals with BsB significantly delayed the onset of disease or protected animals from developing diabetes, with only 13% of treated animals developing diabetes by 35 weeks of age compared to 80% of the animals in the control group. Histopathological analysis of the pancreata of the BsB-treated mice that remained non-diabetic revealed the preservation of insulin-producing β-cells despite the presence of different degrees of insulitis. Thus, a bifunctional protein capable of engaging CTLA-4 and MHCII and indirectly co-ligating CTLA-4 to the TCR protected NOD mice from developing T1D.
Highlights
Cytotoxic T lymphocyte antigen-4 (CTLA-4), known as CD152, is a negative regulator of the T-cell response
Our recent finding that a bifunctional fusion protein comprised of CD80wa and LAG3 (BsB) designed to crosslink CTLA-4 to the T cell receptor (TCR) can induce the production of Foxp3+ Tregs in an allogenic mixed lymphocyte reaction (MLR) led us to examine the potential of this protein to elicit the production of antigen-specific Tregs
We showed that crosslinking CTLA-4 and TCR via MHCII using a novel bispecific fusion protein (BsB) efficiently induced the production of antigen-specific Tregs and the antiinflammatory cytokines, IL-10 and TGF-b in vitro
Summary
Cytotoxic T lymphocyte antigen-4 (CTLA-4), known as CD152, is a negative regulator of the T-cell response. The molecular mechanisms through which CTLA-4 modulates T-cell activity are multifaceted and are thought to occur either intrinsically on conventional T cells or extrinsically through Tregs [8,9,10]. These mechanisms include competing with CD28 for ligand binding [11], inducing the production of the tolerogenic enzyme indoleamine 2,3 dioxygenase in antigen presenting cells (APCs) [12,13], and displacing CD28 from the immunological synapse [14]. Interventions that promote the early engagement of CTLA-4 with its ligands and crosslinking to the TCR result in the premature dampening of key signaling signatures and the consequent inhibition of T-cell activation, leading to T-cell hyporesponsiveness or anergy [18,19,20,21]
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