Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

Bolton, Holly A.; Zhu, Erhua; Terry, Alexandra M.; Guy, Thomas V.; Koh, Woon‐Puay; Tan, Sioh-Yang; Power, Carl; Bertolino, Patrick; Lahl, Katharina; Sparwasser, Tim; Shklovskaya, Elena; Groth, Barbara Fazekas de St

doi:10.1172/jci76031

Cited by 66 publications

(64 citation statements)

References 69 publications

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“…It has been reported that additional antigen presentation by pulmonary APCs, including plasmacytoid DCs, CD8α + DCs and interstitial DCs, sustains antigen‐specific T‐cell responses in the infected lungs . However, CTLA‐4 expressed by Tregs was demonstrated to limit T‐cell priming and proliferation via suppressing costimulation function of DCs . In addition, aggregation of Tregs on DCs in an LFA‐1 dependent‐manner also led to a lethargic state of DCs, thereby a reduced T‐cell priming .…”

Section: Discussionmentioning

confidence: 99%

Memory regulatory T cells home to the lung and control influenza A virus infection

Zanker

Lock

et al. 2019

Immunol Cell Biol

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Memory regulatory T cells (mTregs) have been demonstrated to persist long‐term in hosts after the resolution of primary influenza A virus (IAV) infection. However, whether such IAV infection‐experienced (IAV‐experienced) mTregs differentiate into a phenotypically and functionally distinct Treg subset and what function they play at the infection site remains poorly defined. In this study, we characterized the phenotype, examined the responsiveness and assessed the suppressive function of IAV‐experienced memory Tregs (mTregs). In comparison with inexperienced naïve Tregs (nTregs), mTregs exhibited elevated expression of CD39, CD69, CD103, cytotoxic T lymphocyte‐associated antigen‐4, leukocyte function‐associated antigen‐1 and programmed cell death‐1 and could be activated in an antigen‐specific manner in vitro and in vivo. When mTregs and nTregs were adoptively cotransferred into recipient mice, mTregs had a competitive advantage in migrating to the IAV‐infected lungs. mTregs were more capable of controlling in vitro proliferation of CD4+ and CD8+ T cells and suppressed CD40 and CD86 upregulation on bone marrow‐derived dendritic cells. Adoptively transferred mTregs, but not adoptively transferred nTregs, significantly attenuated body weight loss, lung pathology and immune cell infiltration into the infected lungs after IAV infection. These results suggest that mTregs generated after IAV infection differentiate into a phenotypically distinct and functionally enhanced Treg subset that can be activated in an antigen‐specific manner to exert immunosuppression. We propose vaccination to induce such mTregs as a potential novel strategy to protect against severe IAV infection.

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Section: Discussionmentioning

confidence: 99%

Memory regulatory T cells home to the lung and control influenza A virus infection

Zanker

Lock

et al. 2019

Immunol Cell Biol

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“…[10][11][12][13][14] Conversely, prompt recovery of CD4Tregs can prevent GVHD while also supporting recovery of a broad T-cell repertoire. 12,15 These results suggest that balanced recovery of CD4Tregs, conventional CD4 T cells (CD4Tcons), and CD8 T cells is needed to control alloimmunity and establish immune tolerance. However, the mechanisms that maintain this balance and regulate the recovery of each T-cell population in vivo are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

Alho

Kim

Chammas

et al. 2016

Blood

141

136

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• Homeostatic recovery after allogeneic HSCT favors the production, expansion, and survival of effector T cells over CD4Tregs.• Unbalanced reconstitution of regulatory and effector T-cell subsets contributes to the development of chronic graftversus-host disease.The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. (Blood. 2016;127(5):646-657)

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“…Metrics included weight loss, posture, activity, fur texture, and skin integrity. A clinical aGVHD score was performed on the basis of these five symptoms according to a published staging system [15]. …”

Section: Methodsmentioning

confidence: 99%

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

et al. 2016

BioMed Research International

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Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2 × 107 bone marrow cells and 2 × 107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P < 0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage.

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Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

Cited by 66 publications

References 69 publications

Memory regulatory T cells home to the lung and control influenza A virus infection

Memory regulatory T cells home to the lung and control influenza A virus infection

Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

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