In contrast to aGVHD, where increased understanding of its pathophysiology has led to improved immunomodulatory chemotherapy and cellular therapeutics, the pathophysiology of cGVHD remains poorly defined. The majority of SCT recipients (70 %) now develop cGVHD which represents the major cause of late non-relapse death following SCT. Unfortunately, there is currently no satisfactory therapy for the treatment of cGVHD, which represents an increasing clinical burden. FoxP3+ regulatory T cells (Treg) are crucial for the establishment and maintenance of tolerance after SCT. We have identified the disruption of Treg homeostasis as a critical lesion contributing to cGVHD.(1) However factors which contribute to Treg deficiency and the mechanism by which their absence results in pathology are poorly understood. Recently however, we demonstrated autophagy, as a crucial survival pathway for Treg with a memory like phenotype, and demonstrated the requirement for Treg intrinsic autophagy for efficient Treg reconstitution required for the control of GVHD after SCT.(2)
Importantly, we identified the bone marrow as a niche for autophagy-dependent Treg exhibiting activated/memory like phenotype. Notably, we observed enrichment in the BM of the highly suppressive dependent TIGIT+ Treg population which is marked by the unique capacity to preferentially suppress Th1/Th17 T effector responses while sparing Th2. As outlined in our recent review on BM Treg,(3) although a poorly studied population, the BM Treg appear phenotypically and functionally unique compared to Treg in the periphery. Importantly, we have strong published (2, 3) and unpublished data implicating the functional contribution of BM Treg in the control of cGVHD.
Treg restorative therapies including low dose IL-2 administration and Treg adoptive transfer are currently in use or being trialled in the clinic. While promising results are observed in aGVHD only 50% of cGVHD patients respond. In our preclinical studies the adoptive transfer of Treg attenuated cGVHD pathology, but the effects were only partial. Moreover, in preliminary data we have found IL-2/IL-2R complex administration preferentially expanded peripheral Treg with minimal effects on the BM Treg compartment. These data suggest the BM Treg exhibit cytokine requirements distinct from those in the periphery. Consistent with this, TIGIT+ Treg which are enriched in the BM, express low levels of the IL-2 receptor CD25 compared with splenic Treg, and BM Treg exhibit higher expression of IL-7R, suggesting the BM Treg, like tissue residing memory Treg rely on IL-7 and not IL-2 for their survival. These data suggest that alternative cytokine therapy may preferentially improve BM Treg reconstitution and cGVHD control.
We have recently reported that the defect in Treg homeostasis in cGVHD is downstream of defective antigen presentation within MHC (major histocompatibility complex) class II by antigen presenting cells (APC) particularly by CD11c+ dendritic cells (DC) that is induced by aGVHD.(1) The role of plasmacytoid (pDC) and conventional Dendritic cells (cDC) in Treg maintenance in periphery is well established. Our study and others illustrated the tolerogenic properties of pDC to control aGVHD and to improve antigen specific Treg after SCT. However, we have also reported impaired pDC reconstitution during GVHD.(4) Notably, the DC compartment in the BM is highly enriched in pDC however, their contribution to BM Treg homeostasis at steady state or after SCT remains to be elucidated.
Taken together these studies demonstrate the BM as a niche for highly suppressive Treg required for the control of cGVHD. We hypothesize that after SCT, the BM niche is disrupted, resulting in diminished BM Treg numbers and this represents a primary lesion which directly contributes to cGVHD pathology. Thus we aim to define the factors required for the enrichment and survival of BM Treg to instruct the development of new Treg restorative therapies that promote BM Treg engraftment after SCT.
- Aim 1- Identify a unique molecular signature for BM Treg.
- Aim 2- Determine the cytokine requirement for BM Treg.
- Aim 3- Determine the contribution of DC in Treg maintenance in the BM.
- Leveque-El Mouttie L, Koyama M, Le Texier L, Markey KA, Cheong M, Kuns RD, Lineburg KE, Teal BE, Alexander KA, Clouston AD, et al. Corruption of dendritic cell antigen presentation during acute GVHD leads to a failure of regulatory T-cell homeostasis and chronic GVHD. Blood. 2016.
- Le Texier L, Lineburg KE, Cao B, McDonald-Hyman C, Leveque-El Mouttie L, Nicholls J, Melino M, Nalkurthi BC, Alexander KA, Teal B, et al. Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease. JCI Insight. 2016;1(15):e86850.
- Le Texier L, Lineburg KE, and MacDonald KP. Harnessing bone marrow resident regulatory T cells to improve allogeneic stem cell transplant outcomes. International journal of hematology. 2017;105(2):153-61.
- Banovic T, Markey KA, Kuns RD, Olver SD, Raffelt NC, Don AL, Degli-Esposti MA, Engwerda CR, MacDonald KP, and Hill GR. Graft-versus-host disease prevents the maturation of plasmacytoid dendritic cells. J Immunol. 2009;182(2):912-20.
- Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, Yang C, Towns WH, Lehman A, Johnson AJ, et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest. 2014;124(11):4867-76.