Regulatory T Cells Participate in 4-1BB-Mediated Suppression of Experimental Allergic Conjunctivitis

Abstract

Background: We showed previously that treatment with an agonistic anti-4-1BB Ab during the induction phase of murine experimental allergic conjunctivitis (EC) suppresses the development of this model disease. It was reported that 4-1BB promotes the expansion of regulatory T cells. Here we asked whether the suppression of EC by agonistic anti-4-1BB Ab treatment is mediated by regulatory T cells. Methods: Neonatal BALB/c mice were thymectomized and intraperitoneally injected with anti-CD25 Ab. At 6 weeks of age, these mice were immunized with ragweed (RW) in alum. As a control, immunocompetent BALB/c mice were immunized. Ten days later, the mice were challenged with RW in eye drops and 24 h later, the conjunctivas and spleens were harvested for histological and flow-cytometric analyses, respectively. The agonistic anti-4-1BB Ab or control normal rat IgG was injected intraperitoneally during the induction phase of EC. Results: With regard to immunocompetent mice, anti-4-1BB Ab treatment significantly suppressed the severity of EC as evaluated by conjunctival eosinophil numbers. In contrast, in thymectomized and anti-CD25 Ab-treated mice in which CD4+CD25+ regulatory T cells were efficiently depleted, anti-4-1BB Ab treatment did not affect the severity of EC. Conclusions: These results indicate that CD4+CD25+ regulatory T cells play a critical role in the suppression of EC by anti-4-1BB Ab treatment.

Hu.4-1BB-Fc fusion protein inhibits allergic inflammation and airway hyperresponsiveness in a murine model of asthma

“…Stimulation of the 4-1BB pathway suppressed allergen-specific IgE production and AHR, through deletion of allergen-specific Th2 cells18). Therefore, it seems that 4-1BB could stimulate some regulatory signal to suppress the Th2 response as well21). In a different way, the present study also demonstrated the blockade of 4-1BB may attenuate an allergic inflammation.…”

4-1BB Signaling Synergizes with Programmed Death Ligand 1 Blockade To Augment CD8 T Cell Responses during Chronic Viral Infection

“…If agonistic Abs to 4-1BB are given after Ag priming, this results in augmentation of T cell responses (21, 39). Conversely, administration of Abs agonistic for 4-1BB before or during priming results in suppression of Ag-specific responses (21, 40, 41). This blunting of pathogen-specific responses has been reported to be TNF-α dependent (21).…”

Agonism of 4-1BB for immune therapy: a perspective on possibilities and complications

“…Lastly, an unexpected finding that has been revealed in the field of 4-1BB agonism is the ability to shut off or limit autoimmune and other inflammatory reactions. This has been seen with agonist antibodies injected into murine models of SLE ( 7 , 8 , 136 ), MS ( 31 , 137 ), RA ( 16 , 138 ), conjunctivitis ( 139 , 140 ), IBD ( 141 ), uveitis ( 142 , 143 ), asthma ( 31 , 144 , 145 ), type I diabetes ( 146 ), chronic GVHD ( 147 ), diet-induced obesity ( 148 ), psoriasis ( 149 ), and Sjogren’s syndrome ( 150 ). In general, suppression driven by anti-4-1BB has been seen during the initiation phases of the disease rather than with therapeutic intervention during active disease, although in some models, therapeutic activity has been noted ( 8 , 138 ).…”

“…Two primary mechanisms of 4-1BB-driven suppression have been suggested, either promoting the accumulation and activity of conventional CD4 + Foxp3 + Treg that can express 4-1BB, or more in-line with the tumor and virus literature on 4-1BB, inducing the differentiation or reactivation of CD8 T cells, either into CTL or a type of CD8 + Treg that makes IFN-g and can suppress the normal inflammatory response of CD4 T cells or B cells (16,22,140,141,143,144,(151)(152)(153)(154). Other suppressive activities such as directly driving death of pathogenic effector T cells, expanding MDSC, or promoting regulatory activities in dendritic cells, have also been suggested (19,20,142,147,155).…”