cancers Review Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation Linde Dekker 1, Coco de Koning 2 , Caroline Lindemans 1 and Stefan Nierkens 1,2,* 1 Princess Máxima Center for Pediatric Oncology, Utrecht University, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; [email protected] (L.D.); [email protected] (C.L.) 2 Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; [email protected] * Correspondence: [email protected] Received: 19 June 2020; Accepted: 16 July 2020; Published: 20 July 2020 Abstract: Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes. Keywords: allogeneic hematopoietic cell transplantation; hematological malignancies; immune reconstitution; T cell subsets; serotherapy; conditioning; immunosuppressive therapies; biomarkers 1. Introduction Allogeneic (allo) hematopoietic cell transplantation (HCT) has evolved into the primary and potentially curative treatment procedure for patients with high-risk hematologic malignancies. Hematopoietic cells can be derived from bone marrow (BM), cord blood (CB) or peripheral blood (PB), from either matched unrelated or related donors. The first successful allo-HCT, treating a pediatric patient with lymphoma, occurred in 1975. Although much improvement has been made since then, current long-term survival rates are still around 50–65% due to relapsed disease and adverse effects associated with the procedure that might lead to severe and life-threatening conditions. Risk factors involve graft rejection, acute and chronic graft-versus-host-disease (GvHD) and viral reactivations (VR) [1–4]. These complications have been reported to be a consequence of the chemotherapy or transplant preparative regimens, leading to immune dysregulation and to protracted lymphopenia [5,6]. In addition, the use of T cell-depleting (TCD) serotherapy, such as anti-thymocyte globulin (ATG), in order to decrease the probability of GvHD may have a major impact on immune reconstitution Cancers 2020, 12, 1974; doi:10.3390/cancers12071974 www.mdpi.com/journal/cancers Cancers 2020, 12, 1974 2 of 21 (IR)Cancers and 20 therefore20, 12, x FOR a ffPEERects REVIEW the risk of VR and relapse [7,8]. IR after allo-HCT of myeloid or2 natural of 20 killer (NK) cells is more rapid compared to the slow reconstitution of T cell populations [2,9–11]. Furthermore,of myeloid or T cellsnatural often killer show (NK) a skewedcells is more T cell rapi receptord compared (TCR) repertoireto the slow and reconstitution remain dysfunctional of T cell evenpopulations after the [ recovery2,9–11]. Furthermore, to normal lymphocyte T cells often numbersshow a skewed [12]. Recent T cell receptor studies (TCR) provide repertoire evidence and that T cellremain reconstitution dysfunctional is even key inafter the the development recovery to normal of transplantation-related lymphocyte numbers complications [12]. Recent studies and the patient’sprovide ability evide tonce defeat that T these cell complicationsreconstitution [is4 ,13key–16 in]. the Therefore, development an understanding of transplantation of the- processesrelated involvedcomplications in T cell and reconstitution the patient’s is criticalability forto protectiondefeat these against complications opportunistic [4,13 infections,–16]. Therefore, a sustained an graft-versus-leukemiaunderstanding of the (GvL) processes effect, involved and survival in T chancescell reconstitution after allo-HCT is critical [2–4, 13for]. Here,protection we will against review theopportunistic current understanding infections, a of sustained T cell reconstitution graft-versus- followingleukemia (GvL) allo-HCT effect, as and treatment survival for chances hematological after allo-HCT [2–4,13]. Here, we will review the current understanding of T cell reconstitution following malignancies. We discuss the post-HCT dynamics of different T cell subsets: CD4+ and CD8+ αβ T allo-HCT as treatment for hematological malignancies. We discuss the post-HCT dynamics of cells, γδ T cells, iNKT cells, regulatory T cells (Tregs), MAIT cells and the reconstitution of both naive different T cell subsets: CD4+ and CD8+ αβ T cells, γδ T cells, iNKT cells, regulatory T cells (Tregs), and memory cells. MAIT cells and the reconstitution of both naive and memory cells. 2. T Cell Reconstitution after allo-HCT 2. T Cell Reconstitution after allo-HCT IR of the T cell compartment after HCT is complex and dynamic. T cell reconstitution involves IR of the T cell compartment after HCT is complex and dynamic. T cell reconstitution involves two phases: homeostatic peripheral expansion (HPE) and thymopoiesis. Initial lymphoid immunity is two phases: homeostatic peripheral expansion (HPE) and thymopoiesis. Initial lymphoid immunity providedis provided by passenger by passenger mature mature naive na andive memory and memory T cells T that cells immediately that immediately undergo undergo HPE to HPE replenish to thereplenish T cell compartment. the T cell compartment. HPE is influenced HPE is influenced by either positiveby either or positive negative or Tnegative cell selections, T cell selections, cell source, cytokinecell source, exposure cytokine and exposure TCR stimulation and TCR stimulation [12,17,18]. [ This12,17 thymus-independent,18]. This thymus-independent mechanism mechanism is mainly importantis mainly forimporta earlynt T for cell early reconstitution, T cell reconstitution, since thymopoiesis since thymopoiesis takes attakes least at 6least to 126 to months 12 months to occur. to Thymopoiesisoccur. Thymopoiesis is affected is affected by age-related by age- regenerationrelated regeneration capacity, capacity, therapy-induced therapy-induced cytotoxic cytotoxic insults, steminsults, cell sourcestem cell and source GvHD and [19 –22GvHD]. This [19 process–22]. This results process in the results emergence in the of emergence novel phenotypically of novel naivephenotypically T cells that na haveive maturatedT cells that in have the thymus,maturated simultaneously in the thymus, increasing simultaneously TCR diversity,increasing which TCR is relateddiversity, to a betterwhich clinicalis related outcome to a better [23 clinical–26]. outcome [23–26]. TT cell cell subsets subsets reconstitutereconstitute in distinct distinct ways ways post post-HCT-HCT (Figure (Figure 1), 1which), which is heavily is heavily influenced influenced by bymultiple multiple transplantation transplantation and and patient patient-related-related factors, factors, including including the conditioning the conditioning regimen regimen [12], cell [12 ], cellsource source [27– [2729–],29 donor], donor type type[30], age [30 ],of agerecipient of recipient and donor and [12 donor], HLA [mismatches12], HLA mismatches[31,32], infections [31,32 ], infections[33], graft [33 ],manipula graft manipulationtion [17,34], [17as, 34well], as as well GvHD as GvHD type, type,treatment treatment and andprophylaxis prophylaxis [9]. [9T]. cell T cell reconstitutionreconstitution can can therefore therefore eveneven bebe delayeddelayed for over over 2 2 years years [9 [9,23,23,35,35],], which which is ishighly highly related related to to morbiditymorbidity and and mortality mortality [ 2[–2–44,13,13––1616,36,36,,3737].]. FigureFigure 1. 1.Schematic Schematic overview overview ofof thethe reconstitutionreconstitution of of the the distinct distinct T T cell cell subsets subsets following following allogeneic allogeneic hematopoietichematopoietic cell cell transplantation transplantation (HCT). (HCT iNKT,). iNKT,γδ γδT cellsT cells and and Treg Treg cells cells rapidly rapidly recover recover within within weeks + + toweeks normal to levels normal after levels the after time the of Transplant. time of transplant. CD8 , CD4CD8+, andCD4 memory+ and memory T cell T recovery cell recovery can be can as be early as as oneearly to two as one months, to two and months, these subsets and these subsequently subsets subsequently reconstitute reconstitute within one towithin twoyears.