---
title: "T lymphocytes and natural killer cells in myelodysplastic syndromes: review overview and access no"
id: "frontiers-in-immunology-12-t-lymphocytes-and-natural-killer-cells-in-myelodysplastic-syndromes-function"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-12-t-lymphocytes-and-natural-killer-cells-in-myelodysplastic-syndromes-function"
content_type: "clinical_feed_article"
specialty: "Hematology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1907953"
published_at: "2026-09-04T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# T lymphocytes and natural killer cells in myelodysplastic syndromes: review overview and access no
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-12-t-lymphocytes-and-natural-killer-cells-in-myelodysplastic-syndromes-function
- **Specialty:** [Hematology](https://medichelpline.com/clinical-feed/hematology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1907953)
- **Published At:** 2026-09-04T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source page contains site navigation, journal sections, and metadata but does not include the full review text on **T lymphocytes**, **natural killer (NK) cells**, and **myelodysplastic syndromes (MDS)**. Details of study findings, mechanisms, or therapeutic recommendations were not reported on the captured page. - The page identifies the article as a REVIEW in Frontiers in Immunology and links to the journal and article landing pages, but the main article body is absent from the captured content. - The site content lists journal sections relevant to the topic (for example, **T Cell Biology** and **NK and Innate Lymphoid Cell Biology**) but offers no article-specific subsections, figures, or conclusions. - No author names, abstract, introduction, methods, results, discussion, or references were present in the captured source. Specific data, experimental results, or clinical recommendations therefore cannot be summarized or paraphrased. - Because the source capture is limited to navigation and front-matter, any claims about immune cell function, dysfunction, or therapeutic potential in MDS would be speculative and are not included. - Clinicians and researchers interested in the review should consult the journal landing page or the full article URL to retrieve the full text. The captured page provides links and a DOI-style path that can assist retrieval but did not include full-article content in the provided source. - When the full article is retrieved, summary points to look for include: characterization of **T lymphocyte** subsets in MDS, NK cell phenotypes and cytotoxicity, immune dysregulation mechanisms in bone marrow, and immunotherapeutic strategies tested or proposed for MDS. - The absence of the article body in the source is a limitation of the capture rather than an indication that the article lacks clinical content. Full appraisal requires reading the complete review on Frontiers in Immunology.
## Clinical Analysis & Structured Key Points
Frontiers | T lymphocytes and natural killer cells in myelodysplastic syndromes: function, dysfunction, and therapeutic potential REVIEW article Front. Immunol. , 04 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1907953 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic In Sickness and Health: The Role of Trained Immunity Submission open 5053 views 4 articles Editor & Reviewers Edited by S P Susan Pereira Ribeiro Reviewed by V B Vaishali Bhardwaj L Z Lin-Pierre ZHAO Outline Figures and Tables Figure 1 View in article Table 1 Stage-dependent T-cell and NK-cell immune abnormalities in MDS. View in article Table 2 Clinical trials of T-lymphocyte and NK-cell directed therapies in MDS. View in article REVIEW article Front. Immunol. , 04 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1907953 T lymphocytes and natural killer cells in myelodysplastic syndromes: function, dysfunction, and therapeutic potential J C Justin Cheng 1 E L Eric Leon Tam 2 C O Casey O’Connell 2 * 1. Keck School of Medicine, University of Southern California, Los Angeles, CA, United States 2. Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California, Los Angeles, CA, United States Article metrics View details Abstract Myelodysplastic syndrome (MDS) are clonal myeloid neoplasms that cause cytopenias and can progress to acute myeloid leukemia (AML). Hypomethylating agents (HMA) are the mainstay of treatment for higher risk disease, but they achieve responses in only half of treated patients and complete remission rates are low. Several scientifically based combinatorial regimens have been tested in clinical trials but none has demonstrated a survival benefit over HMA monotherapy. Allogeneic stem cell transplant remains the only curative therapy and is dependent on effective donor lymphocytes for its efficacy. However, access is limited by its toxicity, so alternative approaches are sorely needed. Recent clinical and translational studies have shown that MDS is not only a clonal myeloid disorder, but also associated with immune dysregulation, inflammatory signaling, T-cell repertoire restriction, immune exhaustion, and immune mediated suppression of hematopoiesis. These findings suggest that there is potential for unlocking a novel approach to the treatment of MDS by restoring and/or enhancing the lymphoid immune response. In this review, we discuss the current understanding of the role of normal T lymphocytes in MDS, the causes and manifestations of dysfunctional T lymphocytes as well as the role and dysfunction of natural killer (NK) cells. The role of therapeutic immunosuppression in lower risk MDS is reviewed, as is the impact of HMAs on dysregulated T lymphocytes and NK cells in higher risk disease. We propose that there is tremendous potential for more targeted approaches to engage the lymphoid compartment in addressing the unmet therapeutic need in MDS. 1 Background Myelodysplastic syndromes (MDS), now known as myelodysplastic neoplasms in the most recent classification systems 5 th Edition WHO ( 1 ) and ICC ( 2 ), are a heterogeneous group of myeloid malignancies characterized by ineffective hematopoiesis with recurrent genetic abnormalities and morphologic dysplasia, resulting in cytopenias and variable increase in risk of progression to acute myeloid leukemia. The clinical presentation of MDS also varies significantly, ranging from indolent cytopenias to highly proliferative and genomically complex disease that portends a high risk for leukemic transformation ( 3 ). Because of the heterogeneity in MDS, accurate risk stratification is imperative to provide management and therapy at the appropriate level of intensity. IPSS-R is still the standard on the National Comprehensive Cancer Network (NCCN) guidelines, which incorporates clinical, cytogenetic, and hematological data. Most recently, the IPSS-M module incorporates molecular and NGS data with clinically and cytogenetic variables, and has been well validated ( 4 , 5 ). Lower risk MDS treatment focuses on symptomatic control, cytopenia management, and transfusion independence. Current treatments include supportive care therapies such as erythropoiesis stimulating agents (ESA), the telomerase inhibitor imetelstat ( 6 ), and luspatercept ( 7 ), an erythroid maturation agent targeting transforming growth factor-β (TGF-β) signaling. For higher risk MDS, management is focused on disease modification, delaying AML progression, and for suitable candidates, allogeneic stem cell transplantation for definitive cure. Monotherapy with hypomethylating agents (HMA) remains the therapeutic backbone for high risk MDS, with azacitidine showing improved overall survival compared to conventional care in higher risk MDS ( 8 ). Oral decitabine-cedazuridine also demonstrated clinical activity in MDS from the ASCERTAIN study ( 9 ), but so far, no hypomethylating agent combinations have produced consistent survival benefits. Recently, precision therapy with targeted agents such as ivosidenib ( 10 ) has shown activity in refractory IDH1 mutated MDS, but many patients with MDS lack directly actional genomic targets. Ultimately, allogeneic stem cell transplantation remains the only established curative therapy ( 11 ). However, access is limited due to patient factors such as performance status and comorbidities. Notably, transplant is an immunologic intervention whose efficacy depends on the biology of donor-derived T lymphocytes. Therefore, T lymphocytes play a critical, though incompletely understood, role in the biology of MDS, and when optimally functioning, T lymphocytes are fundamental to the only curative modality currently available. Recent clinical and translational studies have shown that MDS is not only a clonal myeloid disorder, but also associated with immune dysregulation, inflammatory signaling, T-cell repertoire restriction, immune exhaustion, and immune mediated suppression of hematopoiesis ( 12 – 15 ). These findings have led to contrary approaches in targeting T lymphocytes. A subset of hypoplastic MDS with lower-risk patients display clinical and biologic features of immune-mediated marrow failure, including hypocellularity, profound cytopenias, restricted T-cell receptor repertoires, HLA associations ( 16 ), and responsiveness to immunosuppressive therapy ( 17 ). Similarly, autoimmune cytopenias that emerge in the presence of MDS have been successfully treated with immunosuppression ( 18 ). Higher-risk disease, on the other hand, has been associated with immune exhaustion ( 12 ), regulatory T-cell expansion ( 19 ), myeloid-derived suppressor cell (MDSC) activity ( 20 ), checkpoint ligand expression, and impaired antitumor cytotoxicity. Several trials, with variable success rates, have employed immune checkpoint inhibition to stimulate T cell function in higher risk disease. Moreover, mutated immune cells may create a chronic inflammatory state that contributes to the competitive advantage and clonal dominance of MDS-derived hematopoietic cells. In addition to T lymphocytes, dysregulated natural killer (NK) cell cytolytic activity has been observed in MDS. NK cells are mediators of innate immune surveillance against myeloid neoplasms and their cytolytic function has been shown to be impaired in MDS ( 21 ). Particularly, downregulation of the NK cell activating receptors NKp30 and NKG2D along with reduced NK cell function was observed in higher risk disease. NK cells have been shown to express PD-1 and become functionally exhausted under chronic antigenic pressure with upregulation of NK cell activity in PD-1 blockade ( 22 ). As the cellular crosstalk between the lymphoid system and the malignant myeloid clone is systematically deciphered, the MDS treatment paradigm should dramatically expand to enable more potent and targeted engagement of the immune system. In this review, we outline the salient and less overt features of immune dysregulation involving T lymphocytes and NK cells and highlight the potential for immune-targeted therapies to help fill the unmet therapeutic need in MDS. 2 T lymphocytes in the bone marrow microenvironment in MDS 2.1 Normal bone marrow immune architecture Characterization of the normal bone marrow (BM) microenvironment has historically been constrained by technical limitations, particularly the difficulty of isolating non-hematopoietic stromal populations (<0.5% of total cellularity) and sampling bias skewed towards adipocyte-rich populations ( 23 ). The increased use of single-cell transcriptomics and spatial mapping approaches have substantially revised this view, enabling the detailed annotation of distinct cellular BM neighborhoods that coordinate hematopoiesis ( 23 , 24 ). Hematopoiesis is spatially compartmentalized into functional niches rather than occurring within a uniform marrow milieu ( 25 ). Spatial mapping studies have defined an atlas of bone marrow neighborhoods, each with distinct cellular and functional components ( 23 ): an arterio-endosteal niche for early myeloid and granulocyte-monocyte progenitors, an adipocyte niche where HSPCs lie close to adipocytes and adipogenic mesenchymal stem cells (MSC), a sinusoidal niche associated with mature myeloid differentiation, and a peri-arteriolar lymphoid niche enriched for T and B cells ( 26 , 27 ). With age, this organization is progressively remodeled, with expansion of adipocytes, reduced osteolineage support, and increased inflammatory tone. Inflammatory and infectious states can further alter niche organization, promoting myeloid skewing ( 28 ), reducing lymphopoiesis, and creating a permissive baseline for clonal selection ( 29 ). Among these regions, the peri-arteriolar lymphoid niche is spatially and functionally distinct from the HSC-supporting regions. MSCs within this niche are a major source of CXCL12 and IL-7 that serve to support naïve T cells ( 30 ). Arteriolar endothelial cells in this niche provide Notch ligands that contribute to lymphoid commitment and maintenance ( 31 ). As a result, disruption of the niche and these spatial signals is expected to also alter T cell composition and function even before direct exposure to the myeloid clone. 2.2 Niche disruption and spatial remodeling in CHIP and MDS Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly recognized as a principal driver of the early remodeling of the niche architecture ( 29 ). Many of these CHIP-associated driver mutations have independently been associated to promote a pro-inflammatory BM environment through distinct mechanisms. For example, TET2 loss of function in myeloid cells leads to sustained IL-6 overproduction through the loss of HDAC2-mediated transcriptional repression ( 32 ). CHIP-mutated myeloid cells have demonstrated amplified NF-kB activation and exaggerated inflammatory response to pattern recognition receptor stimulation ( 33 ). This inflammatory conditioning may provide a selective pressure for further clonal expansion and establish a low-grade inflammatory marrow environment. This early remodeling is qualitatively distinct from the niche disruption in MDS. Single-cell and spatial profiling of BMs across the continuum has demonstrated that iMSCs first emerge during CHIP and become progressively more prevalent in MDS. However, the functional consequences of this remodeling still differ, with co-culture CHIP-derived HSPCs maintaining robust stromal support programs through CXCL12, CSF1, and GM-CSF at similar levels to healthy controls, whereas MDS-derived HSPCs fail to sustain these programs ( 34 ). As a result of the stromal loss of homeostatic CXCL12+ MSCs, the aforementioned peri-arteriolar lymphoid niche that sustains naive T cell pools is disrupted ( 35 ), establishing the conditions for the T-cell dysfunction and spatial remodeling elaborated below. A defining early event in MDS BM remodeling is the progressive loss of homeostatic CXCL12+ MSCs and their replacement by an inflammatory MSC compartment ( 36 , 37 ). These inflammatory MSCs frequently exhibit activation of canonical inflammatory pathways in NF-kB and IL6 signaling and show reduced ability to support healthy hematopoiesis. MDS MSCs also demonstrate pathological overexpression of CXCL12 in a spatially disorganized pattern. In the healthy marrow, CXCL12 is largely restricted to perivascular regions. However, MSCs in MDS and AML lose their specific homeostatic CXCL12+ niches that support normal HSPCs and instead secrete CXCL12 broadly, which may tether malignant cells and promote their retention in abnormal niches ( 38 ). MDS patients responding to HMAs were seen to have lower CXCL12 expression at remission compared to pre-treatment, suggesting that stromal dysfunction is correlated to disease activity ( 39 ). A key driver of this remodeling is the signaling between dysplastic HSCs and T cells ( 35 ). Activated T cells responding to dysplastic HSCs secrete proinflammatory cytokines that reinforce the inflammatory rewiring of MSCs. Several explanations have been proposed for blast persistence in this niche, including dysregulation of inflammatory signaling pathways in IFN-γ and TNFα ( 40 ) and upregulation of anti-apoptotic BCL-2 family members in MDS clones ( 41 ). In either case, the result is a niche that selectively suppresses normal HSPC repopulation, while mutant HSPCs demonstrate relative resistance to this stress ( 35 ). Lessons from AML and MDS cellular and immunotherapy have suggested that the BM spatial organization of immune cells may also influence response to therapy. In relapsed AML treated with donor lymphocyte infusions, responders exhibited more diverse baseline peri-arteriolar lymphoid niches, while non-responders showed myeloid-dominant neighborhoods with reduced cellular heterogeneity ( 42 ). Responders further shifted towards cytotoxic effector phenotypes whereas non-responders showed enrichment of an exhausted T cell phenotype ( 42 ). In MDS, abnormal CXCL12 secretion was associated with increased malignant cell retention in stromal niches while T cells remained in more distant peri-arteriolar lymphoid compartments, creating a physical separation between cytotoxic T cells and malignant cells ( 36 ). Whether stromal remodeling directly improves active CD-8 T cell access to the malignant compartment remains to be formally demonstrated but offers a spatially coherent explanation. MDS is a disease of both the malignant clone and its immune niche that allows for clonal persistence. The spatial position of T cells relative to malignant cells, the stromal context, and the cellular diversity of their local neighborhood are all relevant to immune dysfunction and therapeutic response, and larger prospective trials that incorporate spatially resolved BM architecture following HMA and combinatorial treatment are needed. 3 Clinical evidence of T cell dysregulation and therapeutic implications MDS arises in the myeloid compartment, but also elicits an adaptive immune component that co-evolves in a chronic inflammatory marrow microsystem, resulting in bidirectional influences. The malignant myeloid clone contributes to shaping T cell biology by generating antigens, altering antigen presentation, remodeling cytokine networks, inducing checkpoint pathways, and recruiting suppressive immune populations ( 43 , 44 ). Simultaneously, the T-cells influence the myeloid clone by suppressing normal hematopoiesis, exerting immune pressure against dysplastic progenitors, selecting for immune evasive subclones, and becoming exhausted as disease progresses. One of the most consistent observations that support T-cell involvement in MDS is the presence of a skewed T-cell receptor repertoire, especially in cytotoxic CD8 positive T cells. CDR3 length typing and flow cytometric analysis of T cel receptor (TCR) Vβ families labelled with specific monoclonal antibodies are the most frequently used assays for the analysis of TCR Vβ repertoire ( 45 ). Early TCR Vβ repertoire studies found differences in T-cell populations in MDS compared to healthy controls that was consistent with antigen-driven expansion rather than random immune activation ( 43 ). Additional studies demonstrated that patients with MDS had more frequent skewing of TCR Vβ profiles than age-matched controls, indicating that T-cell-mediated immune processes is an inherent feature of MDS biology ( 46 ). Cytotoxic T cells have oligoclonal or highly contracted TCR repertoires ( 47 ), supporting the concept that chronic antigen stimulation is common in MDS. With TCR restriction, some T-cell expansions in MDS may recognize antigens related to dysplastic hematopoiesis. Potential antigenic drivers include neoantigens generated by somatic mutations, aberrantly expressed self-antigens, spliceosome-altered peptides, leukemia-associated antigens, stress-induced antigens, or antigens associated with abnormal karyotypes. The strongest clinical examples come from studies of trisomy 8 MDS and WT1-directed immune responses. Sloand et al. demonstrated that autologous lymphocytes could preferentially suppress trisomy 8 hematopoietic progenitors compared with cytogenetically normal progenitors, supporting a model in which cytotoxic T cells can directly recognize and suppress abnormal hematopoietic clones ( 48 ). However, this T-cell response may also contribute to cytopenias by suppressing normal hematopoiesis. This duality is one of the central paradoxes of T-cell biology in MDS. The cytotoxic immune response may restrain the clone while simultaneously damaging hematopoietic function. Inflammatory T-cell subsets also appear to differ by disease stage. Lower-risk MDS has been associated with a pro-inflammatory immune phenotype, with increased Th17 cells, inflammatory cytokines, and apoptotic signaling within the marrow compartment, suggesting that inflammatory T-cell polarization may contribute to ineffective hematopoiesis and marrow injury ( 49 ). This inflammatory state may preferentially damage residual normal hematopoietic stem and progenitor cells while allowing mutant clones with inflammatory resistance or survival advantages to persist, serving as a selective pressure that promotes clonal dominance. As MDS progresses, the T-cell landscape shifts from inflammatory surveillance toward immune dysfunction and immune escape. Regulatory T cells are increased in higher-risk MDS and have been associated with progression to more aggressive disease. The expansion of CD4-positive CD25-high FoxP3-positive regulatory T cells has been shown to be a feature of high-risk MDS and associated with progression ( 19 ). This suggests that the immune system in MDS transitions from a relatively inflammatory, cytotoxic, marrow-suppressive state in lower-risk patients to a more immunosuppressive and tumor progressive state in advanced disease. MDSCs cells add to this immunologic transition. These suppressor populations inhibit T-effector cell proliferation and cooperate with regulatory T cells to impair antitumor immunity. MDSCs from patients with MDS have been shown to suppress T-effector proliferation and MDSC levels correlate with regulatory T-cell numbers in higher-risk disease ( 20 ). MDSCs have been seen to be markedly expanded in the BM of MDS patients and correlated with disease risk and progression ( 50 ). Co-culture of MDSCs with CD8+ T cells resulted in the induction of T cell apoptosis and decreased perforin and granzyme production ( 51 ). In a recent trial of decitabine combined with ATRA vs decitabine alone in 277 MDS-EB patients, treatment with the combination demonstrated a significantly higher ORR (78% vs 51%), reflecting that ATRA-mediated myeloid differentiation may complement HMAs ( 52 ). Though this trial did not specifically measure MDS
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