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. Author manuscript; available in PMC: 2026 Jan 1.
Published in final edited form as: J Immunol. 2025 Jan 1;214(1):192–198. doi: 10.1093/jimmun/vkae007

Immune suppression sustained allograft acceptance requires PD1 inhibition of CD8+ T cells

Hilary Miller-Handley *,†, Gavin Harper *, Giang Pham *, Lucien H Turner *, Tzu-Yu Shao *, Abigail E Russi ‡, John J Erickson §, Mandy L Ford , Koichi Araki *, Sing Sing Way *
PMCID: PMC11904129  NIHMSID: NIHMS2036538  PMID: 40073258

Abstract

Organ transplant recipients require continual immune suppressive therapies to sustain allograft acceptance. Although medication non-adherence is a major cause of rejection, the mechanisms responsible for graft loss in this clinically relevant context among individuals with preceding graft acceptance remain uncertain. Here we demonstrate that skin allograft acceptance in mice maintained with clinically relevant immune suppressive therapies, tacrolimus and mycophenolate, sensitizes hypofunctional PD1hi graft-specific CD8+ T cells. Uninterrupted immune suppressive therapy is required since drug discontinuation triggers allograft rejection, replicating the requirement for immune suppressive therapy adherence in transplant recipients. Graft-specific CD8+ T cells in allograft accepted mice show diminished effector differentiation and cytokine production, with reciprocally increased PD1 expression. Allograft acceptance induced PD1 expression is essential, since PDL1 blockade reinvigorates graft-specific CD8+ T cell activation with ensuing allograft rejection despite continual immune suppressive therapy. Thus, PD1 sustained CD8+ T cell inhibition is essential for allograft acceptance maintained by tacrolimus plus mycophenolate. This necessity for PD1 in sustaining allograft acceptance explains the high rates of rejection in transplant recipients with cancer administered immune checkpoint inhibitors targeting PD1/PDL1, highlighting shared immune suppression pathways exploited by tumor cells and current therapies for averting allograft rejection.

Keywords: rodent (animal), T cells (cells), Transplantation (processes), costimulation (processes)

Introduction

Transplantation remains the definitive therapy for individuals with end organ failure. 2023 was another record breaking year with >46,000 solid organ transplants (>27,000 kidney, >10,000 liver, >4500 heart, >3000 lung) in the US alone (1). The majority were from unrelated donors with the need for life-long immune suppressive therapy as an unavoidable consequence. Reciprocally, non-adherence to immune suppressive therapy remains a primary and consistent leading cause of rejection, allograft failure, and mortality for solid organ transplant recipients (2–7). Despite this consistent causative association, the immunological basis for rejection in this clinically relevant context triggered by immune suppressive therapy cessation after a period of medication induced graft acceptance remains undefined. Current knowledge on how rejection works is instead almost exclusively based on investigating rejection occurring de novo in preclinical models among recipients naive for prior allograft exposure (8–13). However, the immunological basis for de novo rejection is likely distinct from rejection occurring after immune suppression induced allograft acceptance, given changes among adaptive immune components primed by prior allograft stimulation and exposure to immunosuppressive therapies (14–16).

Another consideration relates to specific immune suppressive agents used to induce allograft acceptance which each uniquely change how adaptive immune components respond to allograft. For example, in mice with skin allograft acceptance sustained with anti-CD28 (CTLA4-Ig) plus anti-CD154 (CD40L) IgG, PD1 is highly expressed by graft-specific CD8+ T cells and rejection occurs with co-administration of either anti-PD1 or anti-PDL1 blocking antibodies (17). CTLA4-Ig sustained cardiac allografts are similarly rejected after PDL1 blockade, which is associated with expansion of IFNγ-producing activated CD8+ T cells (18). Pancreatic islet allografts sustained with anti-CD3 IgG also primes PD1 expression in remaining tissue resident CD8+ T cells with rejection after anti-PD1 or anti-PDL1 blocking antibody administration (19). Although these results suggest PD1-mediated CD8+ T cell suppression actively averts allograft rejection, translational applicability remains uncertain since tacrolimus and other calcineurin inhibitors, widely used in clinical transplantation block nuclear factor of activated T cells (NFAT)-dependent T cell activation while simultaneously impeding PD1 expression (20–23). Calcineurin inhibitors like tacrolimus are also often used with mycophenolate (MMF) which selectively suppress lymphocyte proliferation by depleting intracellular guanosine nucleotides (24, 25). For example, tacrolimus combined with MMF significantly reduces rejection incidence compared with tacrolimus alone after orthotopic liver transplantation (26); and this combination is currently prescribed with hospital discharge in >90% kidney, pancreas, or heat allograft recipients, and >80% of liver or lung allograft recipients (27–34). These considerations highlight key knowledge gaps regarding how graft acceptance is more universally achieved with calcineurin inhibitor based immune suppression, and the immunological basis for rejection after non-adherence to clinically relevant tacrolimus based immune suppressive combination therapies.

Materials and Methods

Mice.

Mice engineered for constitutive expression of OVA as a recombinant cell surface protein on the C57BL/6 background, and OT1 TCR transgenic mice containing CD8+ T cells with H-2Kb:OVA257–264 specificity on the CD90.1 congenic background have been described (35–38). Isogenic WT C57BL/6 mice and CD4+ T cell deficient (Cd4−/−; stock #002663) and CD8+ T cell deficient (Cd8a−/−; stock #002665) were purchased from the Jackson Laboratory. All mice were housed under specific pathogen-free conditions at Cincinnati Children’s Hospital Medical Center.

Skin transplantation.

Skin grafting was performed using established protocols (39). For OVA+ donor mice, skin was harvested from the back (between shoulder and hip joints), placed in sterile saline filled dishes, and cut into 1 cm diameter pieces after removal of areas containing new hair growth and fat. Recipient mice were anesthetized with isoflurane was shaved from the shoulder to hip joint in the posterior thorax, and swabbed with chlorhexidine followed by 70% ethanol. An ~1 cm diameter section was excised and pulled off the graft bed, followed by donor graft placement ensuring at least 1–2 mm margins, covered with Vaseline gauze, Tegaderm, and elastic bandage, and monitored daily. Rejection was evaluated using a 5 point scoring scale with intact graft (score 0), first clear signs of rejection (score 1), 25–50% involvement (score 2), 50–75% involvement (score 3) 75–95% involvement (score 4) and complete >95% rejection (score 5) as described (40).

Immune suppressive therapy.

Tacrolimus (FK506; LC Laboratories) was dissolved in DMSO, resuspended in sterile saline to 1 mg/mL final concentration, and IP injected daily to mice for a dose of 10 mg/kg. Mycophenolate (MMF; VistaPharm, Inc) was dissolved in water resuspended in sterile saline to 10 mg/mL final concentration, and IP injected daily to mice for a dose of 100 mg/kg.

In vivo depletion, adoptive cell transfer, stimulation and flow cytometry.

For depleting T cell subsets in vivo, anti-CD8 (250 μg per dose, clone 2.43, BioXcell) or anti-CD4 (250 μg per dose, clone GK1.5, BioXcell) or rat IgG isotype control was administered IP to mice every 7 days. For neutralizing PD1/PDL1, anti-PDL1 IgG (500 μg per dose, clone 10F.9G, BioXcell) or rat IgG2b isotype control was administered to mice every 7 days. For tracking OVA-specific CD8+ T cells, single cell splenocyte suspensions from OT1 CD90.1 donor mice were prepared by gentle spleen tissue dissociation between frosted glass slides, purified for CD8α+ T cells by negative selection using commercially available reagents (Miltenyi Biotec, #130-104-075), with 105 purified CD8+ cells transferred via the lateral tail vein into CD90.2 recipient mice one day prior to transplantation. Adoptively transferred OVA-specific CD8+ T cells were evaluated after skin allograft transplant from OVA+ donors compared with cells in naive control mice each treated with tacrolimus and mycophenolate. Fluorophore-conjugated antibodies used for cell analysis include anti-CD4 (clone RM4–4), anti-CD8a (clone 53–6.7), anti-CD44 (clone IM7), anti-CD90.1 (clone OX-7), anti-CD90.2 (clone 30-H12), anti-TBET (clone 4B10), anti-PD1 (clone 29F.1A12), anti-Ki67 (clone SolA15), anti-EOMES (clone Dan11mag), anti-TNFα (clone MP6-XT22), and anti-IFNγ (clone XMG1.2). Intranuclear staining was performed after cell permeabilization using commercial reagents (eBioscience) according to the manufacturer’s instructions. For cytokine production, axillary lymph node cell suspensions were stimulated with OVA257–264 peptide (1 μM) in DMEM medium (supplemented with 10% fetal bovine serum, 1% L-glutamine, 10 mM HEPES, 1% penicillin-streptomycin) plus brefeldin A (GolgiPlug, BD Bioscience) at 37°C with 5% CO2 for 5 hours and intracellular cytokine staining using commercial reagents (BD Bioscience).

Quantification and statistical analysis.

All statistical analyses were performed with GraphPad Prism (Version 10.1.1). Differences in allograft graft survival was analyzed using the Log-rank (Mantel-Cox) test. Differences between two data sets were evaluated using the student’s T test, and between > 2 groups evaluated using ANOVA. For each analysis, P < 0.05 was taken as statistical significance.

Ethics statement.

All experiments involving vertebrate animals were performed in accordance with Cincinnati Children’s Hospital Institutional Animal Care and Use Committee approved protocols (IACUC2023–1062 and IACUC2021–0007).

Results

Allograft acceptance CD8+ T cell sensitization

To compare the immunological basis for de novo rejection with rejection following a period of allograft acceptance, skin allograft transplantation was performed using mice mis-matched for the model antigen ovalbumin (OVA), which allows precise tracking allograft-specific cells (35, 36). An 1 cm diameter skin patch from OVA+ female donors grafted onto OVA-negative recipients (allogeneic) showed 100% rejection within 21 days compared with no rejection in OVA+ recipients (syngeneic), consistent with results of prior studies demonstrating this limited set of alloantigens are sufficient to drive complete rejection in the absence of immune suppression (Fig. 1A) (36).

Figure 1. CD8+ T cells sensitized by FK506 + MMF sustained allograft acceptance.

Figure 1.

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(A) Transplantation schematic and rejection tempo of OVA+ skin grafts in OVA+ recipients (syngeneic) or OVA-negative C57BL/6 recipients (allogeneic)

(B) OVA+ skin allograft rejection tempo for mice treated daily with FK506 (10 mg/kg) and MMF (100 mg/kg) beginning on the day of transplantation and for 60 days thereafter, and rejection tempo after drug discontinuation.

(C) OVA+ skin allograft rejection tempo in naive recipient mice administered anti-CD8 depleting IgG (clone 2.43; 250 μg every 7 days) or anti-CD4 depleting IgG (clone GK1.5; 250 μg every 7 days) initiated the day prior to transplant compared with no depletion control mice.

(D) OVA+ skin allograft rejection tempo after discontinuation of FK506+MMF in mice administered anti-CD8 depleting IgG (clone 2.43; 250 μg every 7 days) or anti-CD4 depleting IgG (clone GK1.5; 250 μg every 7 days) initiated with immune suppressive therapy discontinuation compared with no depletion control mice. **** P<0.001

To further investigate the clinical scenario of allograft acceptance sustained by immune-suppressive therapies, recipient mice were initiated on daily treatment with FK506 and MMF beginning on the day of transplantation. These experiments showed a majority of FK506+MMF treated mice (21 of 25) develop long-term allograft acceptance, which is contingent on sustained daily FK506+MMF treatment since drug discontinuation triggers rapid and uniform rejection within 20 days (Fig. 1B). Rejection in mice with prior allograft acceptance is reliant on both CD4+ and CD8+ T cells, given delayed rejection tempo in mice administered depleting antibodies targeting each of these cell types with FK506+MMF discontinuation (Fig. 1C). Comparatively, CD8+ T cells are non-essential for de novo rejection given similar rejection tempo in CD8+ cell depleted WT mice or Cd8a−/− mice each compared with CD8+ T cell sufficient WT control mice (Fig. 1D and Supplemental Fig. 1). This distinction was not observed for CD4+ T cells which are equally essential for rejection occurring after FK506+MMF discontinuation and de novo rejection in allograft naive mice (Fig. 1D and Supplemental Fig. 1) (12, 13, 36). Thus, FK506+MMF induced allograft acceptance selectively sensitizes CD8+ T cell which selectively promote rejection after discontinuation of this clinically relevant combination of immune suppressive agents.

Graft-specific CD8+ T cell hypofunction with allograft acceptance

We next focused on how FK506+MMF induced allograft acceptance impacts differentiation and accumulation of graft-specific CD8+ T cells. CD90.1 congenically marked OT1 transgenic CD8+ T cells that express a high affinity TCR with OVA surrogate allograft specificity were transferred into recipient mice one day prior to transplantation (Fig. 2A). These experiments showed graft-specific OT1 CD8+ T cells expand by ~10-fold in the graft-draining axillary lymph node 45 days following transplantation compared with cells in FK506+MMF treated naive control mice without allograft (Fig. 2B). These CD8+ T cells responsive to OVA-allograft stimulation in FK506+MMF treated mice have increased CD44 expression, consistent with cognate antigen stimulation, as well as increased Ki67 levels, indicating proliferation in allograft accepted mice compared to no graft controls (Fig. 2C). Reciprocally, expression of activation-effector promoting transcriptional regulators TBET and EOMES were reduced among graft-OVA-specific CD8+ T cells (Fig. 2C). OT1 T cells produced less TNFα in mice with accepted allografts compared with controls, whereas cells in both groups of mice produced only low levels of IFNγ after OVA257–264 cognate peptide stimulation (Fig. 2D). Interestingly, despite the use of tacrolimus, which is known to suppress PD1 expression (20–23), graft-specific OT1 CD8+ T cells still consistently showed increased (~3-fold) PD1 expression in FK506+MMF treated mice with allograft acceptance. Thus, FK506+MMF induced graft acceptance primes accumulation of PD1hi CD8+ T cells hyporesponsive for effector differentiation and cytokine production.

Figure 2. FK506 + MMF sustained allograft acceptance primes expanded hypofunctional CD8+ T cells.

Figure 2.

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(A) Experimental schematic showing OVA-specific CD8+ T cell (from CD90.1+ OT1 mice) transfer into recipient mice one day prior to skin allogeneic transplantation, and the timing for evaluating the response to allograft.

(B) Accumulation of OVA+ allograft specific donor OT-1 (CD90.1) CD8+ T cells in the draining axillary lymph node for mice with allograft acceptance 45 days after transplant compared with FK506+MMF treated control mice.

(C) OVA-specific (CD90.1) CD8+ T cell expression of each marker from the mice described in panel A.

(D) Percent TNFα and IFNγ producing OVA-specific donor (CD90.1) CD8+ T cells after OVA257–264 peptide stimulation for the mice described in panel A. Each point represents the data from a single mouse, representative of at least two independent experiments each with similar results. *P<0.05; ** P<0.01; *** P<0.005; **** P<0.001

Rejection with reinvigorated graft-specific T cell activation

To investigate the necessity of PD1hi CD8+ T cells for sustaining FK506+MMF induced allograft acceptance, the impacts of in vivo blockade using anti-PDL1 IgG were evaluated. Remarkably despite sustained FK506+MMF therapy, complete rejection still occurred in ~40% (5 of 13) mice with previously accepted allografts within 35 days after initiating anti-PDL1 IgG treatment (P < 0.02 compared with no rejection in rat IgG isotype treated controls) (Fig. 3A). CD8+ T cells are essential since PDL1 blockade induced allograft rejection was overturned with co-administration of anti-CD8 depleting antibodies (rejection only in 1 of 8 mice, P = 0.24 compared with no rejection in rat IgG isotype treated controls (Fig. 3A).

Figure 3. PDL1 blockade overrides FK506+MMF sustained allograft acceptance by reinvigorating graft-specific CD8+ T cell activation.

Figure 3.

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(A) OVA+ skin rejection tempo for allograft accepted mice maintained on daily FK506+MMF administered anti-PDL1 blocking IgG (clone 10F.9G; 500 μg every 7 days), anti-CD8 depleting IgG (clone 2.43; 250 μg every 7 days) or rat IgG2 isotype control 50 days after transplantation.

(B) TBET or PD1 expression levels, and production of TNFα and IFNγ effector cytokines by OVA-specific donor OT-1 (CD90.1) CD8+ cells in the draining axillary lymph node of allograft accepted mice day 7 following administration of anti-PDL1 blocking IgG or discontinuation of FK506+MMF treatment compared with allograft accepted mice sustained on daily FK506+MMF treatment. Each point represents the data from a single mouse, representative of at least two independent experiments each with similar results. *P<0.05; ** P<0.01; *** P<0.005

For evaluating how PD1/PDL1 blockade impacts the activation of graft-specific CD8+ T cells, separate groups of mice transferred OT1 cells prior to transplantation were evaluated at a time point (7 days) prior to when rejection begins after PD1/PDL1 blockade. These experiments showed reinvigorated activation with sharply increased TBET expression, and production of TNFα plus IFNγ, suggesting that PD1 restricts activation of graft-specific CD8+ T cells during FK506+MMF therapy (Fig. 3B). Each of these activation phenotypes were shared, and occurred to an even higher magnitude in FK506+MMF treated with allograft acceptance after discontinuation of FK506+MMF therapy (Fig. 3B). However, an interesting distinction is sharply increased PD1 expression by graft-specific CD8+ T cells reactivated by FK506+MMF discontinuation compared with anti-PDL1 blockade (Fig. 3B), consistent with the dominant role calcineurin inhibitors including FK506 suppress PD1 expression by T cells (20–23). Taken together, these findings demonstrate clinically relevant tacrolimus-based immune suppressive therapy sustains allograft acceptance by PD1 mediated exhaustion of graft-specific CD8+ T cells.

Discussion

Solid organ transplant recipients, and particularly those on calcineurin inhibitors, are at increased risk for developing cancer (41). In turn, immune checkpoint inhibitors targeting PDI/PDL1 are increasingly used for cancer immunotherapy (42, 43). The necessity for PD1 in sustaining allograft acceptance we demonstrate for the widely used clinical combination of tacrolimus plus MMF highlights shared immune suppression pathways exploited by tumor cells and current therapies for averting allograft rejection. We propose this overlap explains the high rates of rejection in transplant recipients with cancer treated with immune checkpoint inhibitors. For example, kidney transplant recipients with squamous cell carcinoma or melanoma showed 42% (29 of 69) acute rejection after administration of immune checkpoint inhibitors compared with only 5% among transplant recipients that did not receive immune checkpoint inhibitor therapy in a multicenter retrospective study (44). A more recent prospective study showed 37% (3 of 8) kidney transplant recipients with advance cutaneous cancer developed graft loss after initiating nivolumab (anti-PD1) (45).

Rejection after initiating anti-PD1 based immune checkpoint inhibitor therapy for cancer also occurs in recipients of liver, heart and lung allografts (46–49), and is therefore not restricted to only one particular tissue graft type. Accordingly our findings after experimental skin transplantation is likely also not restricted only to this tissue, but have broad applicability for how other tissue allografts are maintained with clinically relevant immune suppressive therapies. However, we recognize that tolerance to allograft skin may also have unique considerations, distinct from more vascular tissues including the liver and heart, where tissue ischemia, lack of immediate access to circulating T and antigen presenting cells, together with donor tissue resident leukocytes each may contribute to increasing the threshold for allograft acceptance (8). This is demonstrated by similarly efficient rejection of skin containing major (MHC haplotype) and/or minor (non-MHC antigens) antigen mismatch, whereas rejection of cardiac allografts with minor compared with major histocompatibility mismatch is delayed and incomplete (50). Likewise in CD4+ T cell-deficient (Cd4−/−) mice, primary rejection of fully allogeneic or minor antigen mismatched cardiac tissue is completely eliminated but only delayed for skin allografts mismatched for the same MHC haplotype or minor antigens (13). Therefore, important next steps include investigating whether the threshold for de novo rejection of donor allograft tissue based on vascularization in naive recipients is applicable to rejection that occurs in the more physiological context of immune suppression discontinuation (mimicking clinical non-adherence), the immune mechanisms causing rejection of more vascular donor tissues after allograft acceptance sustained by clinically relevant immune suppressive therapies, and whether our results shown for donor tissue allografts with minor alloantigen mismatch are applicable to complete MHC discordant grafts.

Another interesting consideration relates to the efficiency whereby calcineurin inhibitors such as tacrolimus suppress PD1 expression. Our data show daily treatment of mice at 10 mg/kg dosing, achieving trough concentrations in the low therapeutic range of ~2 ng/ml (51–53), did not completely override allograft induced PD1 upregulation by graft specific CD8+ T cells (Fig. 2C). Nonetheless, PD1 expression was clearly suppressed at this tacrolimus dosage given further increased PD1 levels after FK506+MMF discontinuation (Fig. 3B). In this regard although PD1 can also promote effector CD8+ T cell activation in other stimulation contexts including acute infection (54, 55), graft-specific CD8+ T cell stimulation in mice discontinued from FK506+MMF is dissociated from cell-intrinsic PD1 expression given similar activation among cells in mice treated with anti-PDL1 IgG which retain suppressed PD1 expression levels (Fig. 3B). Accordingly another important area for future investigation is whether increased tacrolimus dosing, achieving higher blood levels especially desired within the first few months after transplantation (52, 53), can more completely eliminate PD1 expression by CD8+ T cells with allograft specificity. If allograft acceptance with tacrolimus or other calcineurin inhibitors in this “PD1-independent” context can be achieved, then the exciting possibility of simultaneously gaining the protective anti-cancer effects of PD1/PDL1 blockade while not reinvigorating the activation of graft specific CD8+ T cells may be realized.

Supplementary Material

1

Key points.

  • Graft-specific CD8+ T cells sensitized by FK506+MMF maintained skin allografts

  • Allograft-acceptance primes hypofunctional PD1hi graft-specific CD8+ T cells

  • FK506+MMF discontinuation or PDL1 blockade reinvigorates CD8+ T cell activation

Acknowledgments

We thank Drs. Lara Danziger-Isakov, David Hildeman and Steve Woodle for helpful discussions.

Funding:

This work was supported by the University of Cincinnati IMSTAR program (H. M-H.), the University of Cincinnati Center for Clinical and Translational Science training program (H. M-H.), the American Society of Transplantation (H. M-H.), the Burroughs Wellcome Fund Investigator in Infectious Disease program (S.S.W), the March of Dimes Foundation Ohio Collaborative for Prematurity Research (S.S.W).

Footnotes

Disclosures

The authors have no financial conflicts of interest.

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