Analysis of the Human T Cell Receptor (TCR) Repertoire from Birth to Old Age Suggests That TCRVβfrequencies Are Established Independent of HLA.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3313-3313
Author(s):  
J. Joseph Melenhorst ◽  
Josette Zeilah ◽  
Edgardo Sosa ◽  
Dean Follmann ◽  
Nancy F. Hensel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Expression ◽  
Rank Order ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Rank Test ◽  
Cell Repertoire ◽  
Cd8 Cells ◽  
Human T Cell

Abstract Human T cell development occurs in two waves of development and proliferation: first, early T cells expressing the TCRb chain but not the α-chain are selected for functional TCRβ protein independent of HLA recognition, a process called β-selection; second, thymocytes expressing both the α- and β-TCR are selected for intermediate affinity for self-MHC/ self-peptide complex. This latter process is referred to as positive selection. We sought to determine whether the peripheral TCRVβ frequencies in the naïve T cell repertoire start off at a fixed rank order with minimal skewing as would be expected from a predominantly β-selected repertoire. A total of 22 TCRVβ proteins was quantitated by flow cytometry in a group of 20 unselected umbilical cord blood (UCB) samples (a kind gift from Dr. P. Rubinstein, NY Blood Center, NY), consisting of >80% naïve T cells as defined by CD27+CD45RA+ staining in CD4+ and CD8+ cells. A common rank order of TCRVβ protein frequencies was found in both CD4 and CD8 T cell subsets (figure 1). Median TCRVβ frequencies in CD4 and in CD8 cells of UCB were statistically not significantly different from the frequencies in adult donor CD4 and CD8 cells (Wilcoxon signed rank test; p > 0.2). Furthermore, the percentages of CD4 cells expressing a particular Vβ correlated significantly in CD8 cells (figure 2) with some Vβ proteins being predominantly expressed by either CD4 (Vβ2, Vβ5.1) or CD8 (Vβ14, Vβ7) cells. Our data therefore conform to the prediction that the TCRVβ frequencies are dominantly shaped by β-selection, and not by interactions of the αβTCR/ co-receptor with MHC/ antigen complexes during thymic selection. Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB

scholarly journals Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy

2021 ◽  
Vol 9 (3) ◽  
pp. e002035
Author(s):  
Kathrin Davari ◽  
Tristan Holland ◽  
Laura Prassmayer ◽  
Giulia Longinotti ◽  
Kenneth P Ganley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
In Vivo Studies ◽  
High Avidity ◽  
Cell Repertoire

BackgroundThe cancer-testis antigen MAGE-A4 is an attractive target for T-cell-based immunotherapy, especially for indications with unmet clinical need like non-small cell lung or triple-negative breast cancer.MethodsAn unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived epitope (GVYDGREHTV) that was properly processed and presented on human leukocyte antigen (HLA)-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high-avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies.ResultsA MAGE-A4-reactive, HLA-A2-restricted T-cell receptor (TCR) was isolated from primed T cells of an HLA-A2-negative donor. The respective TCR-T-cell (TCR-T) product bbT485 was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared with TCR-Ts expressing a TCR derived from a tolerized T-cell repertoire to self-antigens. This natural high-avidity TCR was found to be CD8 co-receptor independent, allowing effector functions to be elicited in transgenic CD4+ T helper cells. These CD4+ TCR-Ts supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells and upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines on tumor-specific stimulation.ConclusionThe extensive pre-clinical assessment of safety and in vivo potency of bbT485 provide the basis for its use in TCR-T immunotherapy studies. The ability of this non-mutated high-avidity, co-receptor-independent TCR to activate CD8+ and CD4+ T cells could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T-cell subsets that goes beyond what is currently tested in the clinic.

The Croonian Lecture, 1992. The key role of the thymus in the body’s defence strategies

1992 ◽  
Vol 337 (1279) ◽  
pp. 105-124 ◽  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cell Receptor ◽  
Division Of Labour ◽  
T Cell Subsets ◽  
Lymphoid Tissues ◽  
Cell Repertoire ◽  
Long Time ◽  
T Cell Selection

For centuries the thymus has remained a mysterious organ with largely unknown functions. The first demonstration of its crucial role in the development of the immune system was reported in 1961, when it was found that mice thymectomized at birth had poorly developed lymphoid tissues, impaired immune reactivities, and an inordinate susceptibility to develop infections. Although thymus lymphocytes were for a long time deemed immunoincompetent, it was shown in 1967 that they could respond to antigen by proliferating to give rise to a progeny of cells which did not secrete antibody (T cells), but which had a remarkable ability to induce bone marrow cells (B cells) to become antibody formers. This was the first unequivocal demonstration of a major division of labour among mammalian lymphocytes. Tremendous progress in our understanding of the function of the thymus and of the T cells derived from it followed. Distinct T cell subsets were characterized and shown to have an essential role in initiating and regulating a variety of immune responses. The ontogenetic events which occurred during their differentiation were mapped, and this allowed studies of the selection of the T cell repertoire. The major histocompatibility complex and associated peptides were shown to govern T cell selection and antigen activation, and the antigen-specific T cell receptor and the genes which code for it were characterized. Future studies should allow some insight into how to activate T cells more effectively for vaccination purposes, and how to switch them off to prevent autoimmune reactions and to induce tolerance to transplanted tissues.

Functional and Numerical T Cell Abnormalities in Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3085-3085
Author(s):  
Mark C. Lanasa ◽  
Marc C. Levesque ◽  
Sallie D. Allgood ◽  
Jon P. Gockerman ◽  
Karen Bond ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Unequal Variances

Abstract Background: Although most malignancies are associated with decreased numbers of circulating T cells, in CLL they are elevated 2 to 4 times normal. Rather than promoting an anti-tumor response, this increased population of T cells may contribute to a tumor microenvironment that fosters progression of the malignant clone. Immunocompetent individuals show a wide repertoire of antigen specificity in both CD4+ and CD8+ T cells, but the T cell repertoire is significantly restricted in CLL. This restriction of the T cell repertoire may be an important cause of infectious morbidity in patients with CLL. To better understand these T cell abnormalities, we enumerated T cell subsets and determined T cell receptor diversity in 18 untreated patients with CLL. Methods: T cell subsets were enumerated from peripheral blood using highly sensitive 6-color flow cytometry. The T cell repertoire was determined for 23 T cell receptor variable β chain families (TCRvβ) in purified CD4+ and CD8+ T cells. These T cell subsets were considered separately because differential restriction of the CD4+ and CD8+ subsets has been reported previously. A PCR-based spectratype assay was used to analyze the length distribution of the TCR complementarity-determining region 3 (CDR3). A limitation of prior reports using spectratype assays was that adequately complex statistical models did not exist to simultaneously analyze the highly diverse vβ families. We addressed this limitation by using a recently-developed statistical method for spectratype analysis (Bioinformatics. 21:3394–400). Briefly, for each vβ family, the divergence from an expected reference distribution was calculated. A divergence coefficient was determined for each vβ family, and the mean divergence of all 23 vβ families was calculated. This allowed for statistical comparisons among individual patients and specific vβ families. To our knowledge, we are the first group to apply this powerful methodology to the analysis of T cell repertoires in patients with CLL. Results: We found both the CD4+ and CD8+ subsets to be expanded (mean #/μL ± SD: 1134 ± 646 and 768 ± 716, respectively; reference normal CD4+ range 401–1532, CD8+ 152–838). The absolute number of CD4+ and CD8+ T cells was greater in patients with higher absolute CLL lymphocyte counts (p = 0.018, r2 = 0.30, and p = 0.23, r2 = 0.09, respectively, linear regression). The CD4:CD8 ratio was lower in IgVH unmutated subjects (mutated 2.6, umutated 1.7, p = 0.09, two-tailed t-test assuming unequal variances). Though prior reports have disagreed on whether CD4+ or CD8+ subsets show greater restriction of clonality, we observed striking clonal restriction of CD8+ but not CD4+ T cells (p < 1×10−7, 2 sided t-test assuming unequal variances). There was a trend toward greater restriction of the CD8+ subset among patients with IgVH unmutated and Zap70+ CLL, but there was no correlation with lymphocyte doubling time. Conclusions: In this cohort of 18 untreated patients with CLL, there was a greater proportional increase compared to reference standards of CD8+ versus CD4+ T cells. However, the increase in CD4+, but not CD8+, T cell numbers was significantly correlated to total CLL lymphocyte count. This observation suggests that expansion of the CD4+ T cell pool observed in CLL is proportional to leukemic burden. The restriction of TCRvβ was limited to CD8+ T cells and that this effect was independent of the size of the abnormal clone. Taken together, these findings suggest different mechanisms of dysregulation of CD4+ and CD8+ T cell subsets in CLL.

Effect of chemoradiation for cervical cancer on transient decrease and variable expansion in T-cell infiltrate and diversity of T-cell repertoire.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11557-11557
Author(s):  
Lauren Elizabeth Colbert ◽  
Stephanie Dorta-Estremera ◽  
Rebecca A. Previs ◽  
Patricia J. Eifel ◽  
Anuja Jhingran ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cell ◽  
Complete Response ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Response To Treatment ◽  
Cell Repertoire ◽  
Cd8 Cells ◽  
Multiparametric Flow Cytometry ◽  
End Of Treatment

11557 Background: The effect of fractionated radiation on intratumoral immune infiltrate is unclear. The purpose of this study was to characterize local immune changes and treatment response during chemoradiation (CRT). Methods: Cervical cancer patients underwent cisplatin based CRT over 5 weeks with brachytherapy. Cervical DNA swabs and cytology brushings were collected at baseline, one week, three weeks and five weeks. Deep T cell receptor β sequencing (TCR; Adaptive, Seattle WA) and multiparametric flow cytometry (MPFC) were performed for each time point. T cell density (TCD) and productive clonality (PC) were analyzed. Cells separated from the tumor brushings were stained and fixed with antibodies to T cell subsets with activation and suppressor markers including CD3, CD4, CD8, Ki67, PD-1, CTLA-4, and ICOS. Changes in T cell subsets were evaluated as percentage of live lymphocytes. Results: Eight patients were evaluated using MPFC. CD4 and CD8 percentages were lowest at one week and subsequently expanded. The percentage of proliferating CD4 (CD4+ Ki67+) was highest at week 5 (1.19%). There was no change in percentage of CD8+ cells expressing PD1, CTLA4 or ICOS over the course of treatment. TCR diversity was assessed for 9 patients. At baseline, week 1, week 3 and week 5, median TCD for all patients were 0.046 (IQR 0.008 to 0.097), 0.021 (IQR 0.005 to 0.043), 0.035 (IQR 0.015 to 0.083), and 0.033 (IQR 0.017 to 0.110). Median productive clonality at each point was 0.05 (IQR 0.06 to 0.02), 0.03 (IQR 0.06 to 0.02), 0.04 (IQR 0.05 to 0.02) and 0.03 (IQR 0.01 to 0.05). PC fold count increased (1.69, SD 1.3) for complete response (CR) patients and decreased 0.3 (SD 0.008) for patients with recurrent (REC) disease (p = 0.1). One TCR sequence was common in 4/9 patients at the end of treatment and six sequences were common in 3/9 patients. Conclusions: Chemoradiation induces a transient decline in tumor infiltrating CD8+ and CD4+ cells, followed by a variable expansion in T-cells at the end of treatment with an increase in proliferation phenotypes. TCR sequencing revealed increase in productive clonality during radiation for patients with a complete response to treatment.

scholarly journals Acquired Mls-1a-like clonal deletion in Mls-1b mice.

1992 ◽  
Vol 175 (2) ◽  
pp. 453-460 ◽  
Author(s):  
M Papiernik ◽  
C Pontoux ◽  
S Gisselbrecht
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Genetic Transmission ◽  
Cd8 Cells ◽  
High Level

BALB/c mice (H-2d, Mls-1b) from one colony progressively modify their T cell repertoire during aging, by deleting T cells that express products of the V beta 6 and V beta 8.1 genes of the T cell receptor. Clonal deletion occurs only in 50% of mice between 27 and 43 wk of age, affecting thymus, spleen, and lymph node T cells. The phenomenon is progressive and seems to affect nearly all thymuses between 14 and 19 wk of age. CD4+CD8- mature T cells are more affected than CD4-CD8+ cells. In the thymus, deletion occurs at the stage of immature J11d+ cells expressing a high level of V beta 6, while J11d+V beta 6low-expressing cells are not modified. Clonal deletion is thus an early phenomenon that deletes cells of the immature generative compartment in the thymus. This Mls-1a-like clonal deletion is associated neither with the expression of an Mls-1a-like antigen that could be identified in mixed lymphocyte reaction in vitro, nor with the presence of Mtv-7, the endogenous mouse mammary tumor virus (MMTV) proviral loci. Spleen cells, bone marrow cells, and total thymocytes injected into newborn thymuses cannot induce V beta 6+ cell deletion. However, newborn thymuses grafted into old BALB/c mice behave like their recipients, suggesting that a new antigen, present in these old BALB/c mice, is indeed able to induce an Mls-1a-like clonal deletion. As other BALB/c colonies tested do not behave in same way, the hypothesis of a new exogenous deleting factor rather than a genetic transmission is likely. This may suggest that acquired clonal deletion is a more common phenomenon than expected, and may be the spontaneous reaction of the immune system to the introduction of a new retrovirus or other superantigen.

scholarly journals Vaccination reshapes the virus-specific T cell repertoire in unexposed adults

2020 ◽  
Author(s):  
Yi-Gen Pan ◽  
Benjamas Aiamkitsumrit ◽  
Laurent Bartolo ◽  
Yifeng Wang ◽  
Criswell Lavery ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Yellow Fever Virus ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Repertoire ◽  
Vaccine Responses ◽  
Human T Cell ◽  
Mhc Tetramers ◽  
Rare Cells

How baseline T cell characteristics impact human T cell responses to novel pathogens remains unknown. Here, we address this question by studying the CD4+ T cell response in unexposed individuals to live attenuated yellow fever virus (YFV) vaccine. We quantified virus-specific population dynamics over time using class II peptide-MHC tetramers. Our data revealed that, even in the absence of known viral exposure, memory phenotype T cells were found in the majority of virus-specific precursors in healthy adults. Pre-existing memory T cells can be divided into two groups; abundant pre-vaccine populations that underwent limited overall expansion and rare cells that generated naive-like responses and preferentially contributed to the memory repertoire after vaccination. Single cell T cell receptor (TCR) sequencing was used to track the evolution of immune responses to different epitopes and showed an association between preservation of unexpanded TCRs before exposure and the robustness of post-vaccine responses. Instead of a further increase in pre-established TCR clones, vaccination boosted the representation of rare TCRs. Thus, vaccine restructures the abundance and clonal hierarchy of virus-specific T cells. Our results link T cell precursor states to post-exposure responses, identifying peripheral education of virus-specific repertoire as a key component of effective vaccination.

scholarly journals Comprehensive analysis of structural and sequencing data reveals almost unconstrained chain pairing in TCRαβ complex

2019 ◽  
Author(s):  
Dmitrii S Shcherbinin ◽  
Vlad A Belousov ◽  
Mikhail Shugay
Keyword(s):  
T Cells ◽  
T Cell ◽  
Structural Data ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Sequencing Data ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Effective Response ◽  
Specific Choice

AbstractAntigen recognition by T-cells is guided by the T-cell receptor (TCR) heterodimer formed by α and β chains. A huge diversity of TCR sequences should be maintained by the immune system in order to be able to mount an effective response towards foreign pathogens, so, due to cooperative binding of α and β chains to the pathogen, any constraints on chain pairing can have a profound effect on immune repertoire structure, diversity and antigen specificity. By integrating available structural data and paired chain sequencing results we were able to show that there are almost no constraints on pairing in TCRαβ complexes, allowing naive T-cell repertoire to reach the highest possible diversity. Additional analysis reveals that the specific choice of contacting amino acids can still have a profound effect on complex conformation. Moreover, antigen-driven selection can distort the uniform landscape of chain pairing, while small, yet significant, differences in the pairing can be attributed to various specialized T-cell subsets such as MAIT and iNKT T-cells, as well as other putative invariant TCRs.

scholarly journals Both intrathymic and peripheral selection modulate the differential expression of V beta 5 among CD4+ and CD8+ T cells.

1992 ◽  
Vol 176 (6) ◽  
pp. 1733-1738 ◽  
Author(s):  
P J Fink ◽  
K Swan ◽  
G Turk ◽  
M W Moore ◽  
F R Carbone
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Gene Encoding ◽  
Cd8 Cells ◽  
Peripheral T Cells

Murine T cells expressing V beta 5 are characterized by (a) intrathymic deletion in the presence of I-E and products of endogenous mouse mammary tumor viruses, and (b) a greater representation in CD8+ relative to CD4+ peripheral T cells, thought to be due to more efficient intrathymic positive selection on class I rather than class II major histocompatibility complex antigens. We have engineered mice that are transgenic for a rearranged gene encoding a V beta 5+ beta chain of the T cell receptor for antigen. Deletion is not predicted in I-E- V beta 5+ transgenic mice, and until the age of 2 wk, the CD4/CD8 ratio of peripheral T cells is &gt; 3:1 and indistinguishable between transgenic and nontransgenic mice. Transgenic mice then show a rapid, age-dependent decline in the ratio of CD4+ to CD8+ T cells in the lymphoid periphery, reaching a low of 1:10 by 7 mo of age. Furthermore, the percent of peripheral CD4+ cells that express the transgene drops with age, reaching a low of about 60% at 7 mo, while the percent of CD8+ cells that express V beta 5 remains greater than 95% at all ages. The lymphoid periphery is implicated in this selection against CD4+ V beta 5+ T cells as it occurs more rapidly in thymectomized transgenic mice, and can be delayed in mice whose peripheral T cells are replaced by recent thymic emigrants after depletion by in vivo treatment with anti-Thy-1 antibodies. These results indicate that the relative expression of V beta 5 in T cell subsets can be influenced not only intrathymically in I-E+ V beta 5+ transgenic mice, but also by events in the periphery, in the absence of I-E expression.

scholarly journals In Vivo Selection of T-Cell Receptor Junctional Region Sequences by HLA-A2 Human T-Cell Lymphotropic Virus Type 1 Tax11-19 Peptide Complexes

2001 ◽  
Vol 75 (2) ◽  
pp. 1065-1071 ◽  
Author(s):  
Mineki Saito ◽  
Graham P. Taylor ◽  
Akiko Saito ◽  
Yoshitaka Furukawa ◽  
Koichiro Usuku ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Virus Type ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Human T Cell ◽  
Cdr3 Region

ABSTRACT Using HLA-peptide tetrameric complexes, we isolated human T-cell lymphotrophic virus type 1 Tax peptide-specific CD8+ T cells ex vivo. Antigen-specific amino acid motifs were identified in the T-cell receptor Vβ CDR3 region of clonally expanded CD8+ T cells. This result directly confirms the importance of the CDR3 region in determining the antigen specificity in vivo.

scholarly journals Characterization of Changes in the T-Cell Receptor Repertoire in Patients with Acute Myeloid Leukemia with Durable Remission Following Allogeneic Stem Cell Transplant

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5186-5186
Author(s):  
Ronald M. Paranal ◽  
Hagop M. Kantarjian ◽  
Alexandre Reuben ◽  
Celine Kerros ◽  
Priya Koppikar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Donor T Cells ◽  
Durable Remission

Introduction: Allogeneic hematopoietic stem-cell transplantation (HSCT) is curative for many patients with advanced hematologic cancers, including adverse-risk acute myeloid leukemia (AML). This is principally through the induction of a graft-versus-leukemia (GVL) immune effect, mediated by donor T-cells. The incredible diversity and specificity of T-cells is due to rearrangement between V, D, and J regions and the random insertion/deletion of nucleotides, taking place in the hypervariable complementarity determining region 3 (CD3) of the T-cell receptor (TCR). Massively parallel sequencing of CDR3 allows for a detailed understanding of the T-cell repertoire, an area relatively unexplored in AML. Therefore, we sought out to characterize the T-cell repertoire in AML before and after HSCT, specifically for those with a durable remission. Methods: We identified 45 bone marrow biopsy samples, paired pre- and post-HSCT, from 14 patients with AML in remission for > 2 years as of last follow-up. We next performed immunosequencing of the TCRβ repertoire (Adaptive Biotechnologies). DNA was amplified in a bias-controlled multiplex PCR, resulting in amplification of rearranged VDJ segments, followed by high-throughput sequencing. Resultant sequences were collapsed and filtered in order to identify and quantitate the absolute abundance of each unique TCRβ CDR3 region. We next employed various metrics to characterize changes in the TCR repertoire: (1) clonality (range: 0-1; values closer to 1 indicate a more oligoclonal repertoire), it accounts for both the number of unique clonotypes and the extent to which a few clonotypes dominate the repertoire; (2) richness with a higher number indicating a more diverse repertoire with more unique rearrangements); (3) overlap (range: 0-1; with 1 being an identical T-cell repertoire). All calculations were done using the ImmunoSeq Analyzer software. Results: The median age of patients included in this cohort was 58 years (range: 31-69). Six patient (43%) had a matched related donor, and 8 (57%) had a matched unrelated donor. Baseline characteristics are summarized in Figure 1A. Six samples were excluded from further analysis due to quality. TCR richness did not differ comparing pre- and post-HSCT, with a median number pre-HSCT of 3566 unique sequences (range: 1282-22509) vs 3720 (range: 1540-12879) post-HSCT (P = 0.7). In order to assess whether there was expansion of certain T-cell clones following HSCT, we employed several metrics and all were indicative of an increase in clonality (Figure 2B). Productive clonality, a measure of reactivity, was significantly higher in post-transplant samples (0.09 vs 0.02, P = 0.003). This is a measure that would predict expansion of sequences likely to produce functional TCRs. The Maximum Productive Frequency Index was higher post-HSCT indicating that the increase in clonality was driven by the top clone (most prevalent per sample). Similarly for the Simpson's Dominance index, another marker of clonality which was higher post-HSCT (0.01 vs 0.0009, P = 0.04). In order to determine whether this clonal expansion was driven by TCR clones shared among patients, we compared the degree of overlap in unique sequences among pre and post-HSCT samples. We found there was very little overlap between samples in the pre and the post-transplant setting and no change in the Morisita and Jaccard Overlap Indices. Conclusions: In conclusion, we show in this analysis an increase in clonality of T-cells following HSCT in patients with AML. This is likely related to the GVL effect after recognition of leukemia antigens by donor T cells and subsequent expansion of these T-cells. These expanded T-cell clonotypes were unlikely to be shared by patients in this cohort, likely reflecting the variety of antigens leading to the GVL effect. This could have direct implications on TCR-mediated immune-therapies given the likely need for a personalized, patient-specific design for these therapies. Figure 1 Disclosures Kantarjian: BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Cortes:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties.

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