Adoptive Immune Effector Cell Therapies in Cancer and Solid Organ Transplantation: A Review.

Cancer is one of the most devastating complications of kidney transplantation and constitutes one of the leading causes of morbidity and mortality among solid organ transplantation (SOT) recipients. Immunosuppression, although effective in preventing allograft rejection, inherently inhibits immune surveillance against oncogenic viral infections and malignancy. Adoptive cell therapy, particularly immune effector cell therapy, has long been a modality of interest in both cancer and transplantation, though has only recently stepped into the spotlight with the development of virus-specific T-cell therapy and chimeric antigen receptor T-cell therapy. Although these modalities are best described in hematopoietic cell transplantation and hematologic malignancies, their potential application in the SOT setting may hold tremendous promise for those with limited therapeutic options. In this review, we provide a brief overview of the development of adoptive cell therapies with a focus on virus-specific T-cell therapy and chimeric antigen receptor T-cell therapy. We also describe the current experience of these therapies in the SOT setting as well as the challenges in their application and future directions in their development.

Adenosinergic Pathway and Linked Suppression: Two Critical Suppressive Mechanisms of Human Donor Antigen Specific Regulatory T Cell Lines Expanded Post Transplant.

Regulatory T cells are an important component of an immune response shaping the overall behavior to potential antigens including alloantigens. Multiple mechanisms have been shown to contribute towards developing and sustaining a immunological regulatory response. One of the described contact dependent suppressive mechanisms regulatory cells have been shown to utilize is through the production of adenosine from extracellular ATP mediated by CD39 and CD73. In this study we demonstrate that the adenosinergic pathway plays a major role in the suppressive/regulatory effects antigen specific regulatory T cell enriched lines (ASTRLs) that have been of expanded ex vivo from stable kidney transplant patients. We have previously shown that these ASTRL cells are capable of suppressing alloimmune responses in vitro and significantly prolonging allograft survival in an animal model of kidney transplantation. For this study nineteen ASTRLs were expanded from 17 kidney transplant patients by repeated stimulation of recipient peripheral blood mononuclear cells with donor specific HLA-DR peptides. All 19 ASTRLs showed upregulation of numerous markers associated with regulatory cells and were able to inhibit donor antigen specific T cell proliferation in a dose dependent fashion. ASTRLs suppressed indirect and direct alloimmune responses compatible with our previous animal study findings. Upregulation of both CD39 and CD73 was observed post expansion and ASTRLs demonstrated extracellular hydrolysis of ATP, indicating functionality of the upregulated proteins. We also showed that inhibition of the adenosinergic pathway using inhibitors of CD39 resulted in abrogation of suppression and increased antigen specific T cell proliferation. This demonstrates that the main mechanism of action of the suppressive activity donor peptide driven ASTRLs generated from kidney transplant patients is the adenosinergic pathway. Furthermore this suggests the possibility that combining infusion of Tregs with other treatments, such as adenosine receptor agonists or increasing CD39 expression in the grafts may further enhance a regulatory response to the allograft and possibly achieve transplantation tolerance.

Exploration of nutritional, antioxidative, antibacterial and anticancer status of Russula alatoreticula: towards valorization of a traditionally preferred unique myco-food.

Healthy food trend is becoming popular these days fueling search for ingredients empowered by pharma-nutritional benefits. In contrast, numerous wild-growing mushrooms are traditionally cherished as health promoting gastronomies in India; although credibility of their effects has so far been limited. Hence the present study aimed to unveil a unique tribal cuisine, Russula alatoreticula, with nutritional, chemical and pharmacological relevance. The outcome demonstrated an excellent alimentary composition with carbohydrate and protein as prominent macronutrients in contrast to fat providing oleic acid (36.66%), linoleic acid (16.84%), palmitic acid (16.01%) and stearic acid (15.31%) indicative of profitable nutritive account. Conversely, ethanolic fraction enriched with phenolics (pyrogallol > cinnamic acid) presented effective antioxidant property in terms of radical scavenging, Fe2+ chelating and reducing power with EC50 ranging from 785 to 2500 µg/ml. Remarkable antibacterial activity was also noted against the tested microorganisms (MIC of 72.5-1560 µg/ml) preferentially targeting Gram-positive one. Besides treatment of the preparation rendered Hep3B proliferation as evident by phenotypic changes, cell cycle interference, reactive oxygen species generation, mitochondrial membrane potential reduction, DNA fragmentation, change in Bax/Bcl2 ratio and activation of caspase9 signifying induction of intrinsic mitochondrial pathway. Thus the study represents R. alatoreticula as a value-added bio-resource that could be featured in food and pharmaceutical industries for betterment of humankind.

A novel antibody for the detection of alternatively spliced secreted KLOTHO isoform in human plasma.

αKlotho is primarily known to express as a transmembrane protein. Proteolytic cleavage results in shedding of the extracellular domain which enters systemic circulation. A truncated form of αKlotho resulting from alternative splicing of the αKLOTHO transcript exists and is believed to be secreted, thereby also entering systemic circulation. Existing ELISA methods fail to distinguish between the two circulating isoforms resulting in inconsistencies in assessing circulating αKlotho levels. We have exploited a unique 15aa peptide sequence present in the alternatively spliced secreted isoform to generate an antibody and show that it is able to specifically detect only the secreted Klotho isoform in human plasma. This finding will facilitate in distinguishing the levels of different circulating Klotho isoforms in health and disease and enhance their potential to serve as a biomarker for CKD and other conditions.

Metallothionein dependent-detoxification of heavy metals in the agricultural field soil of industrial area: Earthworm as field experimental model system.

Earthworms are known to reclaim soil contamination and maintain soil health. In the present study, the concentration of DTPA extractable heavy metals, Cd, Cu, Cr, Pb, and Zn in vermicasts and tissues of the earthworms (anecic: Lampito mauritii; epigeic: Drawida sulcata) collected from the soils of four different industrial sites, Site-I (Sago industry), Site-II (Chemplast industry), Site-III (Dairy industry) and Site-IV (Dye industry) have been studied. The heavy metals in industrial soils recorded were 0.01-326.42 mg kg-1 with higher Cu, Cr, and Zn contents while the vermicasts showed lower heavy metal loads with improved physicochemical properties and elevated humic substances. The higher humic substances dramatically decreased the heavy metals in the soil. The bioaccumulation factors of heavy metals (mg kg-1) are in the order: Zn (54.50) > Cu (17.43) > Cr (4.54) > Pb (2.24) > Cd (2.12). The greatest amount of metallothionein protein (nmol g-1) was recorded in earthworms from Site-IV (386.76) followed by Site-III (322.14), Site-II (245.82), and Site-I (232.21). Drawida sulcata can produce a considerable amount of metallothionein protein than Lampito mauritii as the metallothionein production is dependent upon the presence of pollutants. The molecular docking analysis indicates a binding score of 980 for Cd, Cr and Cu, and 372 for Zn. Pb may bind with a non-metallothionein protein of earthworms and bio-accumulated in the internal chloragogenous tissues. Metallothionein neutralizes the metal toxicity and controls the ingestion of essential elements.

A Tripartite Interaction among the Basidiomycete Rhodotorula mucilaginosa, N2-Fixing Endobacteria, and Rice Improves Plant Nitrogen Nutrition.

Nitrogen (N) limits crop yield, and improvement of N nutrition remains a key goal for crop research; one approach to improve N nutrition is identifying plant-interacting, N2-fixing microbes. Rhodotorula mucilaginosa JGTA-S1 is a basidiomycetous yeast endophyte of narrowleaf cattail (Typha angustifolia). JGTA-S1 could not convert nitrate or nitrite to ammonium but harbors diazotrophic (N2-fixing) endobacteria (Pseudomonas stutzeri) that allow JGTA-S1 to fix N2 and grow in a N-free environment; moreover, P. stutzeri dinitrogen reductase was transcribed in JGTA-S1 even under adequate N. Endobacteria-deficient JGTA-S1 had reduced fitness, which was restored by reintroducing P. stutzeri JGTA-S1 colonizes rice (Oryza sativa), significantly improving its growth, N content, and relative N-use efficiency. Endofungal P. stutzeri plays a significant role in increasing the biomass and ammonium content of rice treated with JGTA-S1; also, JGTA-S1 has better N2-fixing ability than free-living P. stutzeri and provides fixed N to the plant. Genes involved in N metabolism, N transporters, and NODULE INCEPTION-like transcription factors were upregulated in rice roots within 24 h of JGTA-S1 treatment. In association with rice, JGTA-S1 has a filamentous phase and P. stutzeri only penetrated filamentous JGTA-S1. Together, these results demonstrate an interkingdom interaction that improves rice N nutrition.

Environment-friendly management of textile mill wastewater sludge using epigeic earthworms: Bioaccumulation of heavy metals and metallothionein production.

In the present study, Eudrilus eugeniae and Perionyx excavatus were used for vermistabilization of textile mill sludge in different combinations with cowdung for 60 days. A higher percentage of metal removal was observed in earthworm treated mixtures for cadmium (54.5%) followed by copper (36.0%), chromium (37.0%) and zinc (35.9%). Vermistabilized textile mill sludge + cowdung (1:1) showed a maximum percentage increase in total NPK, a significant (P < 0.05) increase in bacteria, fungi, and actinomycetes with a better earthworm survival rate. A higher amount of metallothionein protein was produced by E. eugeniae than P. excavatus. Further, 100% textile mill sludge showed a number of histological abnormalities like degeneration of cells, cellular debris, and uneven cellular compartmentation while textile mill sludge with cowdung showed normal earthworm histology. Results suggest that textile mill sludge + cowdung (1:1) combination is suitable for vermistabilization of textile mill sludge.

Accelerated Allograft Vasculopathy With Rituximab After Cardiac Transplantation.

BACKGROUND: The CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study was a randomized, placebo-controlled, multicenter, double-blinded clinical trial in nonsensitized primary heart transplant (HTX) recipients. OBJECTIVES: The study sought to determine whether B cell depletion therapy would attenuate the development of cardiac allograft vasculopathy. METHODS: A total of 163 HTX recipients were randomized to rituximab 1,000 mg intravenous or placebo on days 0 and 12 post-transplant. Primary outcome was change in percent atheroma volume (PAV) from baseline to 1 year measured by intravascular ultrasound. Secondary outcomes included treated episodes of acute rejection, de novo anti-HLA antibodies (including donor-specific antibodies), and phenotypic differentiation of B cells. RESULTS: There were no significant differences at study entry between the rituximab and placebo groups. Paired intravascular ultrasound measures were available at baseline and 1 year in 86 subjects (49 rituximab, 37 placebo). The mean ± SD change in PAV at 12 months was +6.8 ± 8.2% rituximab versus +1.9 ± 4.4% placebo (p = 0.0019). Mortality at 12 months was 3.4% rituximab versus 6.8% placebo (p = 0.47); there were no retransplants or post-transplant lymphoproliferative disorder. The rate of treated rejection was 24.7% rituximab versus 32.4% placebo (p = 0.28). Rituximab therapy effectively eliminated CD20+/CD19+ B cells followed by a gradual expansion of a CD19- cell population in the rituximab-treated group. CONCLUSIONS: A marked, unexpected increase in coronary artery PAV with rituximab was observed during the first year in HTX recipients. One-year mortality was not impacted; however, longer-term follow-up and mechanistic explanations are required. (Prevention of Cardiac Allograft Vasculopathy Using Rituximab [Rituxan] Therapy in Cardiac Transplantation; NCT01278745).

Biomarkers in Fetomaternal Tolerance.

Multiple mechanisms of tolerance operate in the immune cross-talk at the fetomaternal interface, contributing to successful pregnancy outcome. The cross-talk includes interaction between various cell subsets and between cytokines and molecules of the endocrine system. A depiction of how all these components interact with each other and contribute to tolerance of the fetus is not clearly understood. Dysregulation in one or more of these mechanisms leads to fetal loss. Few effective biomarkers are available that can safely predict fetal loss. This review discusses some potential biomarkers that can predict failure of tolerance at the fetomaternal interface.

Early immune biomarkers and intermediate-term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation-18.

Clinical Trials in Organ Transplantation-18 (CTOT-18) is a follow-up analysis of the 200-subject multicenter heart transplant CTOT-05 cohort. CTOT-18 aimed to identify clinical, epidemiologic, and biologic markers associated with adverse clinical events past 1 year posttransplantation. We examined various candidate biomarkers including serum antibodies, angiogenic proteins, blood gene expression profiles, and T cell alloreactivity. The composite endpoint (CE) included death, retransplantation, coronary stent, myocardial infarction, and cardiac allograft vasculopathy. The mean follow-up was 4.5 ± SD 1.1 years. Subjects with serum anti-cardiac myosin (CM) antibody detected at transplantation and at 12 months had a higher risk of meeting the CE compared to those without anti-CM antibody (hazard ratio [HR] = 2.9, P = .046). Plasma VEGF-A and VEGF-C levels pretransplant were associated with CE (odds ratio [OR] = 13.24, P = .029; and OR = 0.13, P = .037, respectively). Early intravascular ultrasound findings or other candidate biomarkers were not associated with the study outcomes. In conclusion, anti-CM antibody and plasma levels of VEGF-A and VEGF-C were associated with an increased risk of adverse events. Although this multicenter report supports further evaluation of the mechanisms through which anti-CM antibody and plasma angiogenesis proteins lead to allograft injury, we could not identify additional markers of adverse events or potential novel therapeutic targets.

Dynamics of organic matter decomposition during vermicomposting of banana stem waste using Eisenia fetida.

A better understanding of how dynamics of physical and chemical changes occur during vermicomposting process would be helpful for determining the stability and maturity of vermicompost. For improving the knowledge about this issue several instrumental techniques were used in the present study to analyse the physical and chemical changes as a function of vermicomposting time of banana stem waste (BS) spiked with cow dung (CD) in different proportions using earthworm Eisenia fetida. Chemical analysis by ICP-AES showed gradual increase in the plant nutrients (P, Ca, K, Mg, Fe) up to 60 day of vermicomposting in all the treatments. But among different treatments, K, Mg and Fe were considerably higher in the BS2CD1 blend. The FTIR showed strong NO stretching vibration with increasing BS content signifying the presence of nitrate in the final compost. The TG analysis of final BS-CD composts described the lower mass loss (52-55%) in the final compared to the initial stage due to high level of humification by earthworms. The maturity of the final compost was confirmed by DSC analysis which exhibited lowering of relative intensity of exothermic peaks related to the easily degradable material at 320-330 °C and complex organic moieties at 495-530 °C. Decrease in the humification index (Q4/6, Q2/4, Q2/6) at 60 day confirmed the stability of vermicomposts. All the treatments showed <2 mg CO2-C g-1 vermicompost C day-1 respiration rates and >70% germination indices (GI) for rice and pea seeds. These findings defined a clear comparison between the treatments during vermicomposting in terms of stability and maturity and revealed that BS2CD1 can be utilized as nutrient-rich stable compost for enhanced crop production.

Carbon sequestration in macroalgal mats of brackish-water habitats in Indian Sunderbans: Potential as renewable organic resource.

Large influx of excess nutrients into sub-tropical brackish-water habitats is expected to radically affect the algal populations in the heavily populated Sunderbans brackish-water ecozone. Twelve selected brackish-water sites in the Indian Sunderbans were surveyed to investigate the growth performance of mat-forming dominant algal/cyanobacterial macrophytes and their potential for carbon (C) sequestration into hydrologic and pedologic pools. The mats were dominated by particular taxa at different seasons related to physico-chemical properties of the wetland habitats. Different environmental variables and biomass productivity parameters were measured on fortnightly basis to assess the carbon cycle related to dominant algal blooms of the study area. The dominating species at the twelve sites included seven genera (Spirogyra, Rhizoclonium, Ulva, Cladophora, Pithophora, Chaetomorpha) belonging to Chlorophyta, three genera (Polysiphonia, Gracilaria, Catenella) belonging to Rhodophyta and Lyngbya majuscula from cyanobacteria. Multivariate statistical methods indicated that nutrient availability, particularly dissolved P concentration and N:P ratio in the water column, along with salinity in the water column mainly affected biomass yield and C sequestration of mat-forming macrophytes and OC input into water column. However, OC contents of underlying muck proved to be very stable, though small influxes of OC occurred at each bloom. High biomass yields (34-3107 g/m2) of the dominant mat components accumulated enormous stocks of OC, very little of which reaches the pedologic pool. This transient biomass might be utilized as dietary supplements or biofuel feedstocks. Availability of important dietary fatty acids in Spirogyra punctulata, Gracilaria sp., Polysiphonia mollis, Rhizoclonium riparium, R. tortuosum, Pithophora oedogonia and Ulva lactuca was considered as suitability of these species as nutraceuticals. Fatty acid compositions of L. majuscula, Catenella repens, R. tortuosum and Cladophora crystallina were estimated to be applicable for producing biodiesel for usage in sub-tropical climates.

Regulatory T Cells and Kidney Transplantation.

The ability of the immune system to differentiate self from nonself is critical in determining the immune response to antigens expressed on transplanted tissue. Even with conventional immunosuppression, acceptance of the allograft is an active process often determined by the presence of regulatory T cells (Tregs). Tregs classically are CD4+ cells that constitutively express high levels of the IL-2 receptor α chain CD25, along with the transcription factor Foxp3. The use of Tregs in the field of solid organ transplantation is related specifically to the objective of achieving tolerance, with the goal of reducing or eliminating immunosuppressive drugs as well as maintaining tissue repair and managing acute rejection. A key issue in clinical use of Tregs is how to effectively expand the number of Tregs, either through increasing numbers of endogenous Tregs or by the direct infusion of exogenously expanded Tregs. In order to realize the benefits of Treg therapy in solid organ transplantation, a number of outstanding challenges need to be overcome, including assuring an effective expansion of Tregs, improving long-term Treg stability and reduction of risk-related to off-target, nonspecific, immunosuppressive effects related specially to cancer.

Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis.

In patients with peritoneal carcinomatosis cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment strategy. Here, we studied the role of hyperthermic chemotherapy on heat shock protein (HSP) expression and induction of tumor cell death and survival. HSP27, HSP70, and HSP90 combined with effects on tumor cell proliferation and chemosensitivity were analyzed in human colon cancer. Hyperthermic chemotherapy resulted in significant HSP27/HSP70 and HSP90 gene/protein overexpression in analyzed HT-29/SW480/SW620 colon cancer cells and peritoneal metastases from patients displaying amplified expression of proliferation markers, proliferating cell nuclear antigen and antiapoptotic protein Bcl-xL. Moreover, functionally increased chemoresistance against 5-fluorouracil/mitomycin C and oxaliplatin after hyperthermic chemotherapy points to induced survival mechanisms in cancer cells. In conclusion, the results indicate that intracellular HSP-associated antiapoptotic and proliferative effects after hyperthermic chemotherapy negatively influence beneficial effects of hyperthermic chemotherapy-induced cell death. Therefore, blocking HSPs could be a promising strategy to further improve the rate of tumor cell death and outcome of patients undergoing HIPEC therapy.

Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer.

Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.

Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer.

Platelet-derived growth factor (PDGF) and signaling via its receptors plays a crucial role in tumor cell proliferation and thus may represent an attractive target besides VEGF/EGFR-based antibody therapies. In this study we analyzed the influence of PDGF in colorectal cancer. PDGF was expressed intensively in early and even more intensively in late stage primary CRCs. Like VEGF, PDGF enhanced human colon cancer proliferation, and increased oxidative glycolytic activity, and activated HIF1α and c-Myc in vitro. PDGF activated the PI3K/Akt/mTOR pathway while leaving MAPK signaling untouched. Further dissection showed that inhibition of Akt strongly impeded cancer cell growth while inhibition of PI3K did not. MAPK analysis suggested an inhibitory crosstalk between both pathways, thus explaining the different effects of the Akt and PI3K inhibitors on cancer cell proliferation. PDGF stimulates colon cancer cell proliferation, and prevents inhibitor induced apoptosis, resulting in tumor growth. Therefore inhibition of PDGF signaling seems to be a promising target in colorectal cancer therapy. However, due to the multifaceted nature of the intracellular PDGF signaling, careful intervention strategies are needed when looking into specific signaling pathways like PI3K/Akt/mTOR and MAPK.

TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer.

Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance.

Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells.

NK cells are the most abundant lymphocyte population in the feto-maternal interface during gestation. The uterine NK cells (uNK) are transient, have a unique immunophenotype and produce a number of cytokines. These cytokines play an important role in establishment and maintenance of vascular remodeling and tolerance associated with successful pregnancy. The uNK cells also express TIM-3 during gestation and blockade of TIM-3 expression results in fetal loss in mice. In this study we determined the effect of TIM-3 blockade on uNK cells. Specifically we observed surface receptor phenotype and cytokine production by uNK cells following TIM-3 blockade. Our results show that TIM-3 plays a role in regulating the uNK cells and contributes to the maintenance of tolerance at the feto-maternal interface.

Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus.

Tolerance of the fetus by the maternal immune system is regulated through various mechanisms involving the different immune cells, both in the periphery and locally at the feto-maternal interface. The maternal T lymphocytes are aware of the paternal fetal antigens and a state of dynamic T cell homeostasis is maintained in the uterus during gestation, which involves increase in antigen-specific regulatory T cell (Treg) proliferation, increase in apoptosis of antigen-specific effector T cells, and inhibition of excessive inflammation post successful implantation to ensure tolerance to the fetus. The Tregs play an important role in the maintenance of tolerance during gestation. Recently, the inflammatory T helper type 17 (Th17) cells are reported to have a role in loss of tolerance to the fetus. The interaction between costimulatory molecule programmed death 1 (PD1) and its ligand PDL1 is known to play a role in regulating both the Tregs and Th17 cells. Here we discuss how the PD1/PDL1 pathway affects these two T cell populations and its role in feto-maternal tolerance.