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Presumed guilty: Natural killer T cell defects and human disease

  • Authors: Berzins, Stuart , Smyth, Mark , Baxter, Alan
  • Date: 2011
  • Type: Text , Journal article
  • Relation: Nature Reviews Immunology Vol. 11, no. 2 (February 2011 2011), p. 131-142
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  • Description: Abstract | Natural killer T (NKT) cells are important regulatory lymphocytes that have been shown in mouse studies, to have a crucial role in promoting immunity to tumours, bacteria and viruses, and in suppressing cell-mediated autoimmunity. Many clinical studies have indicated that NKT cell deficiencies and functional defects might also contribute to similar human diseases, although there is no real consensus about the nature of the NKT cell defects or whether NKT cells could be important for the diagnosis and/or treatment of these conditions. In this Review, we describe the approaches that have been used to analyse the NKT cell populations of various patient groups, suggest new strategies to determine how (or indeed, if) NKT cell defects contribute to human disease, and discuss the prospects for using NKT cells for therapeutic benefit.
  • Description: C1

Natural killer T cells: Drivers or passengers in preventing human disease?

  • Authors: Berzins, Stuart , Richie, David
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Nature Reviews Immunology Vol. 14, no. 9 (2014), p. 640-646
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  • Description: Natural killer T (NKT) cells are credited with regulatory roles in immunity against cancers, autoimmune diseases, allergies, and bacterial and viral infections. Studies in mice and observational research in patient groups have suggested that NKT cell-based therapies could be used to prevent or treat these diseases, yet the translation into clinical settings has been disappointing. We support the view that NKT cells have regulatory characteristics that could be exploited in clinical settings, but there are doubts about the natural roles of NKT cells in vivo and whether NKT cell defects are fundamental drivers of disease in humans. In this Opinion article, we discuss the uncertainties and opportunities regarding NKT cells in humans, and the potential for NKT cells to be manipulated to prevent or treat disease. © 2014 Macmillan Publishers Limited.

A role for MAIT cells in colorectal cancer

  • Authors: Berzins, Stuart , Wallace, Morgan , Kannourakis, George , Kelly, Jason
  • Date: 2020
  • Type: Text , Journal article , Review
  • Relation: Frontiers in Immunology Vol. 11, no. (2020), p.
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  • Description: MAIT cells are MR1-restricted T cells that are well-known for their anti-microbial properties, but they have recently been associated with different forms of cancer. Several studies have reported activated MAIT cells within the microenvironment of colorectal tumors, but there is conjecture about the nature of their response and whether they are contributing to anti-tumor immunity, or to the progression of the disease. We have reviewed the current state of knowledge about the role of MAIT cells in colorectal cancer, including their likely influence when activated and potential sources of stimulation in the tumor microenvironment. The prospects for MAIT cells being used in clinical settings as biomarkers or as targets of new immunotherapies designed to harness their function are discussed. © Copyright © 2020 Berzins, Wallace, Kannourakis and Kelly.

Lessons learned from an unusual presentation of CD3+, CD56- T-Cell large granular lymphocyte leukemia

  • Authors: Berzins, Stuart , Harrison, Simon , Lee, Robert , Ritz, Nicole , Chan, Andrew , Came, Neil , Curtis, Nigel , Lim, Andrew
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Journal of Clinical Oncology Vol. 28, no. 28 (2010), p. e498- e502
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  • Description: The WHO classification subdivides large granular lymphocytic leukemias (LGLLs) into two subtypes, T and natural killer (NK) LGLLs, with distinct immunophenotypes and clinical presentations.1 Although arising from a common progenitor cell, NK cells are bone marrow–derived innate immune cells capable of cytokine production and cytotoxicity, and T cells are thymic-derived, antigen-specific lymphocytes that express a T-cell receptor (TCR).2 Natural killer T (NKT) cells, a subset of T cells, express NK-associated antigens such as CD16, CD56, and CD57, in addition to a CD1d-restricted, semi-invariant TCR.3 The point at which NKT cells branch from other TCR rearranged cells is not clearly defined. However, this is believed to be mediated through CD1d thymic-dependant signaling in CD4 CD8 double-positive thymocyte precursors.4,5 NK LGLL has a CD3−, CD8+, CD16+, CD56+ phenotype, with variable expression of CD57. It presents in teenagers and young adults with “B” symptoms, lymphadenopathy, hepatosplenomegaly, lymphocytosis, anemia, and thrombocytopenia and typically follows an aggressive clinical course.6 T-cell LGLLs are CD3+, CD8+, CD16+ with a clonal TCR rearrangement and defective Fas (CD95) -mediated apoptosis.7,8 Median age of onset is 55 years, presenting with splenomegaly, neutropenia, and recurrent infections. It is associated with rheumatoid arthritis and follows an indolent and protracted clinical course.9 We describe the case of a teenage patient with T-cell LGLL, who despite having a CD56 immunophenotype, initially showed an aggressive clinical course more in keeping with an NKT leukemia. We discuss the reasoning behind his conservative management and the observed changes in lymphocyte count and serum cytokine/chemokine levels over an 18-month period. There have been no reported cases of an initially aggressive presentation with subsequent spontaneous regression.

An NZW-derived interval on chromosome 7 moderates sialadenitis, but not insulitis in congenic nonobese diabetic mice

  • Authors: Burt, Rachel , Watkins, Laura , Tan, Iris , Wang, Nancy , Quirk, Fiona , Mackin, Leanne , Morgan, Phillip , Zhang, Jian-Guo , Berzins, Stuart , Morahan, Grant , Brodnicki, Thomas
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Journal of Immunology Vol. 184, no. 2 (2010), p. 859-868
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  • Description: Autoimmune lymphocytic infiltration of the salivary glands, termed sialadenitis, is a pathologic feature of Sjögren's syndrome (SjS) that is also prominent in nonobese diabetic (NOD) mice. Genetic factors regulate sialadenitis, and a previous (NOD x NZW)F2 study detected linkage to murine chromosome (Chr) 7. The locus, subsequently annotated as Ssial3, maps to the distal end of Chr7 and overlaps a region associated with type 1 diabetes susceptibility in NOD mice. To examine whether Ssial3 could contribute to both diseases, or was specific for SjS, we generated a congenic mouse strain that harbored an NZW-derived Chr7 interval on the NOD genetic background. This congenic strain exhibited reduced sialadenitis compared with NOD mice and confirmed Ssial3. This reduction, however, did not ameliorate saliva abnormalities associated with SjS-like disease in NOD mice, nor were congenic mice protected against insulitis (lymphocytic infiltration of the pancreatic islets) or diabetes onset. Thus, the Ssial3 locus appears to have a tissue-specific effect for which the NZW allele is unable to prevent other autoimmune traits in the NOD mouse. Anomalous increases for antinuclear Ab production and frequency of marginal-zone B cells were also identified in congenic mice, indicating that theNZW-derived Chr7 interval has a complex effect on the NOD immune system. Copyright © 2010 by The American Association of Immunologists, Inc.

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

  • Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Godfrey, Dale , Ritchie, David , Berzins, Stuart
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Leukemia Vol. 24, no. 3 (2010), p. 592-600
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  • Description: Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function. © 2010 Macmillan Publishers Limited All rights reserved.

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

  • Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Godfrey, Dale , Ritchie, David , Berzins, Stuart
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Leukemia Vol. 24, no. 3 (2010), p. 592
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  • Description: Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function.

Developing NKT cells need their (E) protein

Ex-vivo analysis of human Natural Killer T cells demonstrates heterogeneity between tissues and within established CD4+ and CD4- subsets

  • Authors: Chan, Angela , Leeansyah, Edwin , Cochrane, Andrew , d'Udekem, Yves , Mittag, Diana , Harrison, Leonard , Godfrey, Dale , Berzins, Stuart
  • Date: 2013
  • Type: Text , Journal article
  • Relation: Clinical and Experimental Immunology Vol. 172, no. 1 (2013), p. 129-137
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  • Description: Summary: Our understanding of human type 1 natural killer T (NKT) cells has been heavily dependent on studies of cells from peripheral blood. These have identified two functionally distinct subsets defined by expression of CD4, although it is widely believed that this underestimates the true number of subsets. Two recent studies supporting this view have provided more detail about diversity of the human NKT cells, but relied on analysis of NKT cells from human blood that had been expanded in vitro prior to analysis. In this study we extend those findings by assessing the heterogeneity of CD4+ and CD4- human NKT cell subsets from peripheral blood, cord blood, thymus and spleen without prior expansion ex vivo, and identifying for the first time cytokines expressed by human NKT cells from spleen and thymus. Our comparative analysis reveals highly heterogeneous expression of surface antigens by CD4+ and CD4- NKT cell subsets and identifies several antigens whose differential expression correlates with the cytokine response. Collectively, our findings reveal that the common classification of NKT cells into CD4+ and CD4- subsets fails to reflect the diversity of this lineage, and that more studies are needed to establish the functional significance of the antigen expression patterns and tissue residency of human NKT cells. © 2012 British Society for Immunology.
  • Description: 2003010856

Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family

  • Authors: Chan, Angela , Serwecinska, Liliana , Cochrane, Andrew , Harrison, Leonard , Godfrey, Dale , Berzins, Stuart
  • Date: 2009
  • Type: Text , Journal article
  • Relation: Clinical and Experimental Immunology Vol. 156, no. 2 (May 2009 2009), p. 238-245
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  • Description: Natural killer T cells (NKT) are a regulatory subset of T lymphocytes whose frequency in peripheral blood is highly variable within the human population. Lower than normal NKT frequencies are associated with increased predisposition to a number of diseases, including type 1 diabetes and some forms of cancer, raising the possibility that an increased frequency may be protective. However, there is little or no understanding of how high NKT frequencies arise or, most importantly, whether the potential exists to boost and maintain NKT levels for therapeutic advantage. Here, we provide a detailed functional and phenotypic characterization of the NKT compartment of a human donor with NKT levels approximately 50 times greater than normal, including an analysis of NKT in her immediate family members. The study focuses upon the characteristics of this donor and her family, but demonstrates more broadly that the size and flexibility of the NKT niche is far greater than envisioned previously. This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit.
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Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy

  • Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, Kellie , Quach, Hang , Prince, Henry , Harrison, Simon , Godfrey, Dale , Ritchie, David , Berzins, Stuart
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Clinical and Experimental Immunology Vol. 175, no. 1 (2014), p. 49-58
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  • Description: The causes of multiple myeloma (MM) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with MM, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with MM and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for MM, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive MM had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation.

Acute exercise leads to regulation of Telomere-Associated genes and MicroRNA expression in immune Cells

  • Authors: Chilton, Warrick , Marques, Francine , West, Jenny , Kannourakis, George , Berzins, Stuart , O'Brien, Brendan , Charchar, Fadi
  • Date: 2014
  • Type: Text , Journal article
  • Relation: PloS One Vol. 9, no. 4 (2014), p. e92088
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  • Description: Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. Funding NHMRC

Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population

Modulation of TCR signalling components occurs prior to positive selection and lineage commitment in iNKT cells

  • Authors: Dinh, Xuyen , Stanley, Dragana , Smith, Letitia , Moreau, Morgane , Berzins, Stuart
  • Date: 2021
  • Type: Text , Journal article
  • Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
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  • Description: iNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4+CD8+ (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24hiCD44loNKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development, and separates the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment. © 2021, The Author(s). **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Stuart Berzins” is provided in this record**

Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes

  • Authors: Evrard, Maximilien , Wynne-Jones, Erica , Peng, Changwei , Kannourakis, George , Berzins, Stuart
  • Date: 2021
  • Type: Text , Journal article
  • Relation: Journal of Experimental Medicine Vol. 219, no. 1 (2021), p.
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  • Description: Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes. © 2021 Evrard et al.

Human blood MAIT cell subsets defined using MR1 tetramers

Control points in NKT-cell development

  • Authors: Godfrey, Dale , Berzins, Stuart
  • Date: 2007
  • Type: Text , Journal article
  • Relation: Nature Reviews Immunology Vol. 7, no. 7 (July 2007 2007), p. 505-518
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  • Description: CD1d-dependent natural killer T (NKT) cells are a unique T-cell subset with the ability to regulate the immune system in response to a broad range of diseases. That low NKT-cell numbers are associated with many different disease states in mice and humans, combined with the fact that NKT-cell numbers vary widely between individuals, makes it crucial to understand how these cells develop and how their numbers are maintained. Here, we review the current state of knowledge of NKT-cell development and attempt to highlight the most important questions in this field.
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The BH3-Only Proteins Bim and Puma Cooperate to Impose Deletional Tolerance of Organ-Specific Antigens

  • Authors: Gray, Daniel , Kupresanin, Fiona , Berzins, Stuart , Herold, Marco , O'Reilly, Lorraine , Bouillet, Philippe , Strasser, Andreas
  • Date: 2012
  • Type: Text , Journal article
  • Relation: Immunity Vol. 37, no. 3 (September 2012), p. 451-462
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  • Description: Although the proapoptotic BH3-only protein, Bim, is required for deletion of autoreactive thymocytes, Bim-deficient mice do not succumb to extensive organ-specific autoimmune disease. To determine whether other BH3-only proteins safeguard tolerance in the absence of Bim, we screened mice lacking Bim as well as other BH3-only proteins. Most strains showed no additional defects; however, mice deficient for both Puma and Bim spontaneously developed autoimmunity in multiple organs, and their T cells could transfer organ-specific autoimmunity. Puma- and Bim-double-deficient mice had a striking accumulation of mature, single-positive thymocytes, suggesting an additional defect in thymic deletion was the basis for disease. Transgenic mouse models of thymocyte deletion by peripheral neoantigens confirmed that the loss of Bim and Puma allowed increased numbers of autoreactive thymocytes to escape deletion. Our data show that Puma cooperates with Bim to impose a thymic-deletion checkpoint to peripheral self-antigens and cement the notion that defects in apoptosis alone are sufficient to cause autoimmune disease.
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The NF-κB1 transcription factor prevents the intrathymic development of CD8 T cells with memory properties

Methodological optimisation of thymocyte isolation and cryopreservation of human thymus samples

  • Authors: Hagen, Ruth , Xu, Calvin , Koay, Hui-Fern , Konstantinov, Igor , Berzins, Stuart , Kedzierska, Katherine , van de Sandt, Carolien
  • Date: 2024
  • Type: Text , Journal article
  • Relation: Journal of Immunological Methods Vol. 528, no. (2024), p.
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  • Description: Premature lymphocytes develop into non-autoreactive, mature naïve CD4+ or CD8+ T cells in the thymus before entering the circulation. However, in-depth characterization of human thymocyte development remains challenging due to limited availability of human thymus samples and the fragile nature of thymocyte populations. Thymocytes often do not survive cryopreservation and thawing procedures, especially the fragile CD4+CD8+ double positive population. It is generally recommended to use fresh human thymus tissue on the day of excision to avoid any biases in thymocyte composition. This hampers the possibility to perform multiple experiments on the same thymus sample. To establish how the thymocyte viability and composition can be maintained, we compared two thymocyte isolation methods used for human and/or mice thymi, three cryopreservation methods in combination with our most gentle thawing technique. Based on our findings we established that fresh human thymi remain viable in cold storage for up to two days post-surgery without compromising thymocyte composition. Thymocytes can be cryopreserved if required, although the CD4+CD8+ double positive populations may be reduced. Our study provides thoroughly optimized methods to study human thymocyte development over a considerable time-frame post-surgery. © 2024 The Authors