PD-1 Suppresses Protective Immunity to <i>Streptococcus pneumoniae</i> through a B Cell–Intrinsic Mechanism

McKay, Jerome T; Egan, Ryan; Yammani, Rama D.; Chen, Lieping; Shin, Tahiro; Yagita, Hideo; Haas, Karen M.

doi:10.4049/jimmunol.1401673

Cited by 34 publications

(35 citation statements)

References 44 publications

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“…Evidence of selective activation, expansion, and differentiation of these antigen-binding cells in immunized PD-1 −/− mice, but not WT mice, clearly supports the notion that the PD-1 regulatory axis controls B-1 responses to mucins. PD-1 suppresses humoral responses to classical TI-2 antigens (10,11,13). PD-1 is transiently upregulated by antigen-specific B-1b cells (11,13,43) and thereby contributes to suppression of antigen-specific B cell division, isotype switching, and Ab production during TI-2 responses (11,13).…”

Section: Discussionmentioning

confidence: 99%

“…PD-1 suppresses humoral responses to classical TI-2 antigens (10,11,13). PD-1 is transiently upregulated by antigen-specific B-1b cells (11,13,43) and thereby contributes to suppression of antigen-specific B cell division, isotype switching, and Ab production during TI-2 responses (11,13). However, dBSM shares functional characteristics of both TI-2 (multivalent carbohydrate display) and TD (protein backbone) antigens.…”

Section: Discussionmentioning

confidence: 99%

“…Naïve spleen and peritoneal B cells were purified using negative depletion as described (11,13). B cells from immune mice were purified using EasySep untouched mouse B-cell purification (Stem Cell Technologies) with biotinylated F4/80 antibody included.…”

Section: Methodsmentioning

confidence: 99%

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PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

Haro

Littrell

Yin

et al. 2016

Cancer Immunology Research

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Tn is a carbohydrate antigen uniquely exposed on tumor mucins and thus, an ideal target for immunotherapy. However, it has been difficult to elicit protective antibody responses against Tn antigen and other tumor associated carbohydrate antigens. Our study demonstrates this can be attributed to PD-1 immuno-inhibition. Our data show a major role for PD-1 in suppressing mucin- and Tn-specific B-cell activation, expansion, and antibody production important for protection against Tn-bearing tumor cells. These Tn/mucin-specific B cells belong to the innate-like B-1b cell subset typically responsible for T cell–independent antibody responses. Interestingly, PD-1–mediated regulation is B cell–intrinsic and CD4+ cells play a key role in supporting Tn/mucin-specific B cell antibody production in the context of PD-1 deficiency. Mucin-reactive antibodies produced in the absence of PD-1 inhibition largely belong to the IgM subclass and elicit potent antitumor effects via a complement-dependent mechanism. The identification of this role for PD-1 in regulating B cell–dependent antitumor immunity to Tn antigen highlights an opportunity to develop new therapeutic strategies targeting tumor associated carbohydrate antigens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

Haro

Littrell

Yin

et al. 2016

Cancer Immunology Research

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“…2009; McKay et al. 2015) the TLR4-dependent increase in PD-1 during CKD progression may be one mechanism by which CKD patients become more susceptible to bacterial infections (Naqvi and Collins 2006; Dalrymple and Go 2008). Although inflammation and immunosuppression are seemingly divergent aspects of the innate immune response, they may be regulated by TLR4 at multiple checkpoints, analogous to NFκB participating in not only the onset of TLR-mediated inflammation, but also during the resolution of inflammation (Ghosh and Hayden 2008).…”

Section: Discussionmentioning

confidence: 99%

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

et al. 2015

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Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD.

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“…B cell-expressed PD-1 plays a major role in suppressing Ab production to pneumococcal polysaccharide, as well as other T cell– independent type 2 antigens (TI-2 Ags) and tumor-associated carbohydrate Ags (48–50). Evidence supports that PD-1 specifically induced on Ag-specific B-1b cells suppresses B cell proliferation and differentiation to IgG-producing cells (48). Nonetheless, spontaneous PC-specific Ab production, as well as adaptive immune responses to PC may be differentially regulated (23, 30, 51).…”

Section: Introductionmentioning

confidence: 99%

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5–Dependent Mechanism

McKay

Haro

Daly

et al. 2017

The Journal of Immunology

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B-1 cells produce natural antibodies which provide an integral first line of defense against pathogens while also performing important homeostatic housekeeping functions. In this study, we demonstrate programmed cell death 1 ligand 2 (PD-L2) regulates the production of natural antibodies against phosphorylcholine (PC). Naïve PD-L2-deficient (PD-L2−/−) mice produced significantly more PC-reactive IgM and IgA. This afforded PD-L2−/− mice with selectively enhanced protection against PC-expressing non-typeable Haemophilus influenzae (NTHi), but not PC-negative NTHi, relative to wild type mice. PD-L2−/− mice had significantly increased PC-specific CD138+ splenic plasmablasts bearing a B-1a phenotype, and produced PC-reactive Abs largely of the T15 idiotype. Importantly, PC-reactive B-1 cells expressed PD-L2 and irradiated chimeras demonstrated B cell-intrinsic PD-L2 expression regulated PC-specific Ab production. In addition to increased PC-specific IgM, naïve PD-L2−/− mice and irradiated chimeras reconstituted with PD-L2−/− B cells had significantly higher levels of IL-5 – a potent stimulator of B-1 cell Ab production. PDL2 mAb blockade of wild type B-1 cells in culture significantly increased CD138 and Blimp1 expression and PC-specific IgM, but did not affect proliferation. PDL2 mAb blockade significantly increased IL-5+ T cells in culture. Both IL-5 neutralization and STAT5 inhibition blunted the effects of PDL2 mAb blockade on B-1 cells. Thus, B-1 cell-intrinsic PD-L2 expression inhibits IL-5 production by T cells and thereby limits natural Ab production by B-1 cells. These findings have broad implications for the development of therapeutic strategies aimed at altering natural Ab levels critical for protection against infectious disease, autoimmunity, allergy, cancer, and atherosclerosis.

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PD-1 Suppresses Protective Immunity to Streptococcus pneumoniae through a B Cell–Intrinsic Mechanism

Cited by 34 publications

References 44 publications

PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5–Dependent Mechanism

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