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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Immunol. Author manuscript; available in PMC Feb 1, 2012.
Published in final edited form as:
PMCID: PMC3128994

TIGIT has T cell intrinsic inhibitory functions1


Costimulatory molecules regulate the functional outcome of T cell activation and disturbance of the balance between activating and inhibitory signals results in increased susceptibility to infection or the induction of autoimmunity. Like the well-characterized CD28/CTLA-4 costimulatory pathway, a newly emerging pathway consisting of CD226 and TIGIT has been associated with susceptibility to multiple autoimmune diseases. Here we studied the role of the putative co-inhibitory molecule TIGIT and show that loss of TIGIT in mice results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. TIGIT is thought to indirectly inhibit T cell responses by the induction of tolerogenic dendritic cells. By generating an agonistic anti-TIGIT antibody, we demonstrate that TIGIT can inhibit T cell responses directly independent of APCs. Microarray analysis of T cells stimulated with agonistic anti-TIGIT antibody revealed that TIGIT can act directly on T cells by attenuating TCR driven activation signals.

Keywords: TIGIT, Costimulation, T cell regulation, EAE


Recent genome-wide association scans have linked a costimulatory molecule, CD226, to multiple autoimmune diseases in humans (1). CD226, together with TIGIT (T cell immunoglobin and ITIM domain)2, forms an emerging pathway, that has striking similarities to the well known costimulatory CD28/CTLA-4 pathway. As in the B7-CD28/CTLA-4 pathway, CD226 and TIGIT bind the same set of ligands (CD155 and CD112) and CD226 is a positive regulator of T cell responses, while TIGIT inhibits them (2). A recent study suggested that TIGIT does not have any direct effects on T cells, but instead, acts on dendritic cells (DCs)3 through the ligand CD155. TIGIT interaction with CD155 induced tolerogenic DCs that impaired T cell proliferation and inhibited IFN-γ production from responding T cells (3). However, although TIGIT contains two ITIMs in its cytoplasmic tail, it has not been elucidated whether TIGIT can directly inhibit T cell responses. This is partly because of the lack of relevant reagents that allow direct evaluation of its role in T cells.

Here we used TIGIT−/− mice and generated anti-TIGIT monoclonal antibodies to analyze the function of TIGIT in T cells. We show that loss of TIGIT results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. Furthermore, by generating an agonistic anti-TIGIT antibody, we demonstrate that TIGIT has T cell intrinsic effects and that signals through TIGIT directly inhibit T cell activation.

Materials and Methods


C57BL/6-Tg(Tcra2D2, Tcrb2D2) (2D2) mice have been previously described (4), TIGIT−/− mice were obtained from ZymoGenetics, Inc. (Seattle, WA) and were generated by Ozgene.com (http://www.ozgene.com) using ES cells derived from C57BL/6 mice. C57BL/6 (B6) mice were purchased from the Jackson Laboratories, B6.SJL-Ptprca/BoAiTac (CD45.2 B6) mice from Taconic (Hudson, NY) and Armenian Hamsters from Harlan (Indianapolis, IN). Animals were kept in a conventional, pathogen-free facility at the Harvard Institutes of Medicine (Boston, MA) and all experiments were carried out in accordance with guidelines prescribed by the Institutional Animal Care and Use Committee (IACUC) at Harvard Medical School.

T cell activation and proliferation

Cells were cultured in DMEM with 10% FCS, 50 μM mercaptoethanol, 1 mM sodium pyruvate, nonessential amino acids, L-glutamine, penicillin and streptomycin. For in vitro T cell activation, CD4+ and CD8+ T cells were isolated using anti-CD4 or anti-CD8 beads (Miltenyi) and stimulated with plate bound anti-CD3 (145-2C11, 2 μg/ml) and anti-CD28 (PV-1, 2 μg/ml) or soluble anti-CD3 (0.025 μg/ml) with irradiated splenocytes as APCs. Where indicated, cells were labeled with 2 μM CFSE. For costimulation with agonistic anti-TIGIT, CD4+MHC II cells were sorted by flow cytometry and stimulated with plate bound anti-CD3 (0.5 μg/ml), anti-CD28 (0.5 μg/ml) and anti-TIGIT (clone 4D4, 50 μg/ml) or isotype control (Biolegend). To determine proliferation, cells were pulsed with 1 μCi of 3H-thymidine (Perkin Elmer) after 48h and incubated for an additional 18h before incorporation was analyzed using a β-counter (1450 Microbeta, Trilux, Perkin Elmer).


Where indicated, 105 TCR transgenic CD4+ T cells were transferred i.v. 1 day prior to immunization. Mice were immunized s.c. with 100 μg of myelin oligodendrocyte glycoprotein (MOG)435–55 peptide (MEVGWYRSPFSRVVHLYRNGK) emulsified in CFA. Organs were collected 7 or 8 days later, cells were re-stimulated with MOG35–55 peptide and proliferation was determined by 3H-thymidine incorporation. Frequencies of MOG-specific cells were determined after 5 days of re-stimulation with 30 μg/ml MOG35–55 peptide using MHC class II tetramers (I-A(b)) loaded with MOG35–55 or CLIP peptide (PVSKMRMATPLLMQA, control) (20 μg/ml, 1.5h at room temperature; NIH tetramer core facility, Atlanta). Cytokine concentrations in culture supernatants were determined by ELISA (IL-17) or cytometric bead array (BD Biosciences, other cytokines).

Experimental autoimmune encephalomyelitis (EAE)5

EAE was induced by s.c. immunization of mice with 10–15 μg of MOG35–55 peptide emulsified in CFA followed by 100ng of pertussis toxin (List Biological Laboratories) i.v. on days 0 and 2 and classical clinical signs of EAE were scored as described previously (4). Atypical signs were scored as 0.5 for each of the following: dyskinesia, ataxia, clasping phenotype.

Generation of anti-TIGIT antibodies

Armenian hamsters and TIGIT−/− mice were immunized with recombinant mouse TIGIT tetramers (Zymogenetics, Inc.) by a combination of s.c. and food pad immunization and booster injections. Draining lymph nodes were fused with Sp2/0-Ag14 cells, selected in HAT (hypoxanthine/aminopterin/thymidine) medium and supernatants were screened for specificity by ELISA and flow cytometry using TIGIT-transfectants (Zymogenetics, Inc.).

Flow cytometry

Cells were stained in PBS, 0.1% sodium azide, 0.5% BSA (20 minutes at 4°C). Antibodies were from BioLegend, eBioscience (anti-Foxp3), BD Biosciences (7AAD) or generated as part of this study (anti-TIGIT, clone 1G9). Samples were acquired on a FACSCalibur or LSRII flow cytometer (BD Biosciences) and analyzed using the FlowJo software (Tree Star).

Quantitative RT-PCR

RNA was extracted with RNAeasy mini Kits (Qiagen, Valencia, CA) and was analyzed by real-time PCR (RT-PCR) according to the manufacturer’s instructions (Applied Biosystems, Carlsbad, CA). Primers-probe mixtures were: CD226 (Mm01301769m1); β-actin (Mm00446968-m1); TCRα (Mm01313019_g1); CD3ε (Mm01179194_m1); PLCγ1 (Mm01247293_m1); IL-2Rγ (Mm00442885_m1); CD25 (Mm01340213_m1); BCL-XL (Mm00437783_m1). For TIGIT primers and probe were: forward primer: 5′-CTGATACAGGCTGCCTTCCT-3′, reverse primer: 5′-TGGGTCACTTCAGCTGTGTC-3′, probe: 5′-AGGAGCCACAGCAGGCACGA-3′ (FAM, TAMRA).


Cells were harvested after 24h stimulation and RNA was isolated using RNeasy kits (Qiagen). GeneChip hybridization, staining, and scanning of the arrays were performed by the Partners HealthCare Center for Personalized Genetic Medicine (Cambridge, MA; http://www.hpcgg.org) according to the manufacturer’s instructions (Affymetrix). Summarization of probe set intensity, background correction and normalization was done using the Bioconductor implementation of the GCRMA algorithm (5). Expression signals were compared using linear regression (6). In the single probe set analysis we used an alpha level of 0.05 and regarded fold change ≥ 1.4 or ≤ 0.71 as significant. Ingenuity pathway analysis (Ingenuity® Systems) was used to identify groups of genes or pathways that show enrichment in significant molecules (fold change ≥1.2, p-value ≤ 0.1) and GSEA (7) to identify significant coordinate expression (using the KEGG database (Kyoto Encyclopedia of Genes and Genomes), http://www.genome.jp/kegg). We created an additional two pathways (“T cell activation”, Suppl. table II and “T cell survival”, Suppl. table II). The microarray data is deposited at http://www.ebi.ac.uk/arrayexpress with the accession number E-MEXP-2847.

Results and Discussion

TIGIT is expressed upon initial T cell activation

TIGIT is upregulated on human T cells upon activation and expressed on human memory and regulatory T cells (Tregs)6 (3). However, due to lack of reagents the expression of TIGIT on mouse T cells has not been analyzed. To monitor TIGIT surface expression, we generated a panel of TIGIT-specific monoclonal antibodies in TIGIT−/− mice and screened them for TIGIT-specificity. Clone 1G9 showed the best binding properties when screened by ELISA (Suppl. Fig. 1A). It also specifically stained TIGIT-transfected P815 cells and activated primary mouse T cells (Suppl. Fig. 1B andC) as assessed by flow cytometry. We therefore used the 1G9 anti-TIGIT antibody to analyze the kinetics of TIGIT expression and compared its expression to its costimulatory receptor CD226 in mouse T cells.

TIGIT expression was induced upon stimulation and mRNA levels steadily increased during the first 3 days of activation in both CD4+ and CD8+ T cells (Fig. 1A). Interestingly, surface expression of TIGIT peaked at 24h and then decreased over time, even though mRNA levels kept increasing, suggesting that TIGIT expression was tightly regulated post-transcriptionally (Fig. 1B). This could be due to degradation and possibly also to receptor internalization, which would functionally decrease surface TIGIT levels and limit inhibitory signals at the initiation of the T cell response. Despite a decrease in CD226 mRNA after 24h, CD226 cell surface protein expression was transiently upregulated on CD4+ T cells upon activation. While CD8+ T cells constitutively express CD226 (8), T cell activation induced only minimal changes in CD226 mRNA and cell surface protein expression on CD8+ T cells (Fig. 1).

Figure 1
Expression of CD226 and TIGIT on T cells

TIGIT −/− mice show augmented T cell responses upon immunization

To begin to determine the role of TIGIT in vivo, TIGIT−/− mice were immunized s.c. with MOG35–55 and the T cell response was analyzed 8 days later. When compared to B6 mice, T cells from TIGIT−/− mice displayed increased dose-dependent proliferation upon re-stimulation with antigenic peptide. T cell hyperproliferation was observed in draining lymph nodes (LN)7 and spleens of TIGIT−/− mice as well as in non-draining LN, whereas no response was observed in the non-draining LN of wild type mice (Fig. 2A). Consistent with these results, tracking of antigen-specific CD4+ T cells with MOG35–55/IAb tetramers, confirmed that TIGIT−/− mice had higher frequencies of MOG-specific T cells in these organs (Fig. 2B). Similarly, MOG35–55 re-stimulated splenocytes and LN cells from TIGIT−/− mice produced higher levels of pro-inflammatory cytokines including IL-6, IFN-γ and IL-17 (Fig. 2C). Interestingly, TIGIT−/−-derived cells produced reduced basal levels of IL-10, which is in line with previous reports indicating that TIGIT induces IL-10 production in DCs (3). However, in addition to reduced basal levels, IL-10 was also not induced by antigen-specific stimulation in TIGIT−/− cultures, suggesting that production of IL-10 by T cells is also impaired. In summary, these data demonstrate that TIGIT acts as a negative regulator of T cell responses in mice.

Figure 2
TIGIT−/− mice show increased T cell responses upon immunization

TIGIT−/− mice are more susceptible to EAE

Since CD226 has been genetically liked to susceptibility to autoimmunity (1) and TIGIT, which shares the same ligands, seems to act as an inhibitory molecule, we next tested whether the absence of TIGIT affects the development of autoimmunity. We immunized TIGIT−/− and B6 mice for induction of EAE with suboptimal doses of MOG35–55 (10–15μg), where B6 mice could not develop severe EAE but TIGIT−/− mice might display full-blown disease. Indeed, in contrast to B6 mice the vast majority of TIGIT−/− mice developed severe EAE (Fig. 3A), supporting the notion of TIGIT as a co-inhibitory molecule and suggesting an important role for the CD226/TIGIT pathway in regulating autoimmune responses.

Figure 3
TIGIT−/− mice are more susceptible to EAE

In order to assess the role of TIGIT in the control of spontaneous autoimmunity, we crossed the TIGIT−/− mice to MOG35–55-specific TCR transgenic mice (2D2 mice) (4). 2D2 mice do not develop spontaneous EAE but mostly develop spontaneous optic neuritis. If TIGIT is an inhibitory molecule, we reasoned that in the absence of TIGIT, 2D2 mice might develop EAE spontaneously. Indeed, 2D2 × TIGIT−/− mice showed atypical signs of neurologic dysfunction as early as 28 days after birth (Fig. 3B) and with advancing age all 2D2 × TIGIT−/− mice displayed dyskinesia, ataxia and a clasping phenotype (9). Some of the 2D2 mice also showed these atypical symptoms. However, onset was strongly delayed and, in contrast to 2D2 × TIGIT−/− mice, 2D2 mice never progressed to classical paralytic disease. These results emphasize the role of TIGIT as a negative regulator of T cell responses and indicate that TIGIT plays a role in limiting autoimmune responses and loss or dysfunction of this co-receptor may likely contribute to susceptibility to autoimmunity.

TIGIT has T cell intrinsic effects

We next tested if the augmented T cell responses displayed by TIGIT−/− mice were exclusively mediated through APCs or whether TIGIT can also directly affect T cells. In order to discriminate the effects mediated by APCs from those that are T cell intrinsic, we isolated CD4+ T cells from B6 and TIGIT−/− mice, labeled them with CFSE and stimulated them with either B6 or KO APCs together with anti-CD3. Analysis of B6 T cell proliferation confirmed that TIGIT could mediate effects indirectly through APCs, as KO APCs were better at promoting proliferation than their wild type counterparts (Suppl. Fig. 2A and B). However, when wild type APCs were used to stimulate B6 or TIGIT−/− T cells, the TIGIT−/− T cells also showed increased proliferation. The strongest proliferation, however, was observed when combining KO APCs with KO T cells, suggesting that TIGIT has synergistic roles on T cells and APCs.

To dissect T cell intrinsic and indirect effects of TIGIT in vivo, we transferred 2D2 or 2D2 × TIGIT−/− CD4+ T cells into CD45.1 B6 hosts. These mice were immunized with MOG35–55 and the T cell response was analyzed 7 days later. Despite comparable T cell expansion in vivo, TIGIT−/− T cells showed increased proliferation upon re-stimulation with antigenic peptide and produced higher levels of pro-inflammatory cytokines (Suppl. Fig. 2C–E). Importantly, 2D2 × TIGIT−/− recipients also showed reduced IL-10 levels, confirming a T cell intrinsic defect in IL-10 production in TIGIT−/− T cells.

To exclude any effects that might be due to conditioning of the APCs we analyzed the T cell intrinsic effects of TIGIT in an APC-free system. To completely eliminate any cells other than T cells from our experiments, we tested our panel of TIGIT-specific antibodies for functional agonistic activity in vitro. Generating agonistic antibodies directed against Ig superfamily members, such as CD28, has proven to be a challenging endeavor and when tested for functional effects, none of our antibodies showed agonistic activity. We therefore generated a second panel of TIGIT-specific antibodies in Armenian Hamsters and screened them for specificity (Fig. 4A–C) and functional activity. Out of these antibodies, only one clone (4D4) affected T cell proliferation in vitro. Clone 4D4 proved to be agonistic as the addition of plate bound 4D4 to anti-CD3/anti-CD28 stimulated T cells inhibited their proliferation (Fig. 4D). Importantly, when TIGIT−/− T cells were stimulated with agonistic anti-TIGIT no functional inhibition in T cell proliferation was observed, confirming the specificity of the antibody. Since no APCs were present in these in vitro experiments, these data clearly demonstrate that TIGIT can act directly on T cells.

Figure 4
TIGIT has T cell intrinsic effects

TIGIT engagement modulates T cell activation

Co-inhibitory receptors on T cells are fundamental constituents of the adaptive immune system necessary to limit T cell responses in order to prevent chronic T cell activation, immunopathology and autoimmunity, as demonstrated by the autoimmune-mediated lethality of the CTLA-4−/− mice as well as the therapeutic approaches using CTLA-4-Ig (10–12). While all co-inhibitory molecules have the ability to dampen T cell activation, they differ in potency, kinetics of expression and the cellular pathways they alter. In order to understand how each co-inhibitory molecule alters T cell responses, it is critically important to elucidate which signaling pathways are modulated by each of them.

We used a whole genome microarray approach to identify the pathways affected by TIGIT engagement and compared the gene expression in B6 CD4+ T cells stimulated with agonistic anti-TIGIT 4D4 antibody to that of isotype and TIGIT−/− controls (Suppl. Table I). We found the majority of the differences observed to be small, likely representing alterations of pathways induced by T cell activation rather than separate pathways that are induced through TIGIT (Suppl. Fig. 3A). Ingenuity pathway analysis (IPA)8 and gene set enrichment analysis (GSEA9 (7, 13)) were used to identify pathways that are differently regulated if TIGIT is engaged and in line with the functional effects we observed upon TIGIT activation, we found several pathways that are associated with T cell activation and cell cycle progression to be enriched in the controls, indicating that TIGIT down-regulates these pathways. An overlay of the microarray data with the T cell activation pathway showed that a number of molecules involved in TCR and CD28 signaling are significantly down-regulated upon TIGIT engagement and that many other key molecules involved although not significantly decreased show the same trend (Suppl. Fig. 4A). Furthermore, we generated a gene set comprising key molecules for the TCR and CD28 signaling pathways as well as cell cycle progression and could verify that this gene set is enriched in the control group using both GSEA and IPA (Suppl. Fig. 3B). In addition, we have verified the TIGIT-mediated downregulation of three key molecules of this pathway by RT-PCR (Suppl. Fig. 4C). TIGIT seems to block productive T cell activation by directly acting on TCR expression itself as engagement of TIGIT induced a down-regulation of the TCR alpha chain as well as molecules that comprise the TCR complex. Therefore, in contrast to other co-inhibitory receptors like e.g. PD-1 that interfere with processes that are further downstream in the TCR induced signaling cascade (14), TIGIT acts upstream.

While TIGIT engagement down-regulated TCR activation pathways it did not inhibit cellular processes in general. We found expression of cytokine receptors that are associated with T cell maintenance (i.e. IL-2R, IL-7R and IL-15R) as well as anti-apoptotic molecules, such as BCL-XL, to be up-regulated by TIGIT (Suppl. Fig. 4B). As for the T cell activation, we used RT-PCR to validate the differential expression of key genes of this pathway (Suppl. Fig. 4D) and generated a core gene set for T cell maintenance and survival, which was found to be enriched in the TIGIT stimulated sample using GSEA and IPA (Suppl. Fig. 3C). In summary, TIGIT also inhibits T cell responses directly by targeting molecules that are upstream in the T cell activation process while promoting T cell maintenance and survival, thus although T cells are not activated and expanded the cells do not undergo anergy and are not deleted from the repertoire.

Our data support the idea that TIGIT is an inhibitory molecule and loss of TIGIT in vivo increases T cell proliferation, pro-inflammatory cytokine production and accelerates development of autoimmunity. In addition to inhibiting T cell responses via APCs, TIGIT can act directly on T cells, as an agonistic anti-TIGIT antibody was able to inhibit T cell proliferation in the absence of any other cell type. Overall, our results support the notion that TIGIT is an inhibitory molecule that, in addition to affecting APC function, suppresses T cell responses directly in a T cell intrinsic manner.

While TIGIT deficiency per se does not result in the induction of spontaneous autoimmunity or tissue inflammation, loss of TIGIT in a susceptible background can results in autoimmune disease as was observed in 2D2 × TIGIT−/− mice, which spontaneously developed EAE. TIGIT might therefore regulate the threshold of T cell activation and may be involved in the maintenance of peripheral tolerance. Finally, the genetic linkage of the CD226/TIGIT pathway to a number of human autoimmune diseases (1) further indicates that this pathway plays an important role in limiting autoimmune responses and loss or dysfunction of TIGIT may likely contribute to susceptibility to autoimmune diseases.

Supplementary Material

Supplementary Figures

Supplementary Legends

Supplementary Tables


We would like to thank ZymoGenetics, especially Dr. Steve Levin, for the kind provision of various reagents including the TIGIT−/− mice and recombinant proteins. We thank Vance Morgan and the Partners HealthCare Center for Personalized Genetic Medicine for performing the microarrays, Deneen Kozoriz for cell sorting, Sharon Kunder for technical assistance and members of the Kuchroo and Sharpe group for discussions.


1This work was supported by grants P01AI056299, P01AI039671 and R01NS035685 from NHI to V.K.K. and A.H.S.. N.J. is supported by the Swiss National Science Foundation and the Janggen-Pöhn-Stiftung, J.P.H. by the Juvenile Diabetes Research Foundation and Wellcome Trust, B.B. is a Swedish Research Council Fellow and S.S. is supported by Deutsche Forschungsgemeinschaft (DFG).

2TIGIT: T cell immunoglobin and ITIM domain

3DC: dendritic cell

4MOG: myelin oligodendrocyte glycoprotein

5EAE: experimental autoimmune encephalomyelitis

6Treg: regulatory T cell

7LN: lymph node

8IPA: ingenuity pathway analysis

9GESA: gene set enrichment analysis


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