Biological Differences in Peripheral T-Cell Lymphomas Identified by DNA Microarrays.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3012-3012
Author(s):  
Beatriz Martinez-Delgado ◽  
Manisha Bahl ◽  
Marta Cuadros ◽  
Victoria Fernandez ◽  
Javier Benitez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Resting Cells ◽  
T Cell Lymphomas ◽  
Infiltrating Cells ◽  
Peripheral T Cell Lymphomas

Abstract Peripheral T-cell lymphomas (PTCL) constitute a heterogeneous and aggressive group of tumors whose pathogenic alterations remain largely unknown. They show great morphologic, immunophenotypic and clinical differences. Expression profiling has been demonstrated to be a useful tool for the molecular classification of tumours. We used DNA microarrays (Affymetrics, Lymph_DX) to look for molecular differences in peripheral T-cell lymphomas. We analysed the expression of 19 pathologically confirmed PTCL (11 PTCL, unspecified (u) and 8 angioimmunoblastic, AILT). A time-course of stimulation with anti-CD3 and anti-CD28 was performed in CD4+ and CD8+ isolated peripheral blood lymphocytes, and the gene expression of tumors was compared with resting and stimulated normal T-cells. Cases of classical Hodgkin’s lymphoma, with which PTCL may be confused, were included. Gene expression of PTCL revealed several clusters of genes with biological significance showing differential expression within the tumors. We defined a “Cytotoxic Response” cluster characterized by the expression of cytotoxic molecules PRF1 and GZMB and GZMH, a “B-cell-related genes” cluster which included B-cell specific genes PAX5 or CD19, and an interesting “Resting-cells genes” cluster. These three clusters were negatively correlated with a “Proliferation” signature. On the other hand, the “Proliferation” signature significantly correlated with the expression of TNFRSF8 (CD30) (r=0.63, p=0.003) and the expression of CD3G (r=0.51, p=0.022). Other interesting genes were also found associated specifically to the proliferation of PTCL. Comparison between PTCLu and AILT showed differences in the expression of CD21 and other genes reflecting the higher presence of dendritic cells in AILT, and also revealed differences in expression of relevant chemokines, such us CXCL5, CXCL13 and CCL19. Intriguingly, compared with normal CD4 and CD8 T-cells, PTCL showed lower expression of most of the typical genes associated with T-cell biology, suggesting that PTCL often lose the common genetic program of T-cells. PTCL expression profiles are difficult to interpret due to the significant proportion of other infiltrating cells accompanying the tumor. Our results showed that microarrays are a helpful tool to dissect the PTCL expression profile, identifying those genes expressed by infiltrating cells and those expressed by tumor cells.

Identification of a Proliferation Signature Related to Survival in Nodal Peripheral T-Cell Lymphomas

2007 ◽  
Vol 25 (22) ◽  
pp. 3321-3329 ◽  
Author(s):  
Marta Cuadros ◽  
Sandeep S. Dave ◽  
Elaine S. Jaffe ◽  
Emiliano Honrado ◽  
Roger Milne ◽  
...  
Keyword(s):  
T Cell ◽  
Inflammatory Response ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Inverse Correlation ◽  
Microarray Platform ◽  
Cellular Processes ◽  
T Cell Lymphomas ◽  
Insight Into ◽  
Peripheral T Cell Lymphomas

Purpose Nodal peripheral T-cell lymphomas (PTCLs) constitute a heterogeneous group of neoplasms, suggesting the existence of molecular differences contributing to their histologic and clinical variability. Initial expression profiling studies of T-cell lymphomas have been inconclusive in yielding clinically relevant insights. We applied DNA microarrays to gain insight into the molecular signatures associated with prognosis. Materials and Methods We analyzed the expression profiles of 35 nodal PTCLs (23 PTCLs unspecified and 12 angioimmunoblastic) using two different microarray platforms, the cDNA microarray developed at the Spanish National Cancer Centre and an oligonucleotide microarray. Results We identified five clusters of genes, the expression of which varied significantly among the samples. Genes in these clusters seemed to be functionally related to different cellular processes such as proliferation, inflammatory response, and T-cell or B-cell lineages. Regardless of the microarray platform used, overexpression of genes in the proliferation signature was associated significantly with shorter survival of patients. This proliferation signature included genes commonly associated with the cell cycle, such as CCNA, CCNB, TOP2A, and PCNA. Moreover the PTCL proliferation signature showed a statistically significant inverse correlation with clusters of the inflammatory response (P < .0001), as well as with the percentage of CD68+ cells. Conclusion Our findings indicate that proliferation could be an important factor in evaluating nodal PTCL outcome and may help to define a more aggressive phenotype.

CS-1 Is Expressed in Nasal Type NK/T Cell Lymphomas and Angioimmunoblastic T-Cell Lymphomas: Implications for Targeted Therapy with Elotuzumab (HuLuc63).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1779-1779
Author(s):  
Eric D Hsi ◽  
Roxanne Steinle ◽  
Balaji Balasa ◽  
Audie Rice ◽  
Young-Hyeh Ko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Expression Profiling ◽  
Nasal Type ◽  
T Cell Lymphomas ◽  
Nk T Cells ◽  
Nk T Cell ◽  
Peripheral T Cell Lymphomas

Abstract Background: CS-1 (CRACC, SLAMF7, CD319) is a member of the signaling lymphocyte activating molecule-related receptor family. It is highly and uniformly expressed on the cell surface of benign and malignant plasma cells. We have recently reported the generation of elotuzumab (formerly known as HuLuc63), a humanized antibody targeting CS-1, which is currently in phase 1 trials in relapsed multiple myeloma. Lower levels of CS-1 have also been reported on NK cells and NK-like T-cells (NK/T). CS-1 expression in NK and T-cell lymphomas - aggressive lymphomas for which no effective therapy exists - is unknown. Here, we examined the expression of CS-1 in normal NK/T cells and in a series of NK and peripheral T-cell lymphomas (PTCL). Methods: CS-1 expression in normal NK and T-cells were assessed by gene expression profiling. Flow cytometry (FACSCalibur, Becton Dickinson) was performed on blood from normal samples using a directly conjugated Alexa-488 elotuzumab. Archival formalin-fixed, paraffin-embedded tissues from PTCLs, including angioimmunoblastic T-cell lymphomas (AITL) and nasal type NK/T cell lymphomas were tested for CS-1 expression using the a paraffin-reactive 1G9 monoclonal antibody and automated immunohistochemistry (IHC, Ventana Medical Systems). Results: Gene expression profiling showed CS-1 expression in purified NK and NK/T cells. We confirmed cell surface expression of CS-1 protein on normal blood NK and NK/T cells (n=18 samples) by flow cytometry with Alexa-488-HuLuc63. The majority of normal NK and NK/T cells expressed CS-1 (mean% positive and standard deviation of 96% +/− 4% and 71 % +/− 24%, respectively). We then evaluated tumor samples from patients with nasal type NK/T cell lymphoma as well as other peripheral T-cell lymphomas by IHC. Biopsies from 13 patients (5 from the United States, 8 from Korea) with nasal type NK/T cell lymphomas were evaluated by IHC. 12 of 13 (92%) patient samples expressed CS-1 with most cases showing a majority of cells positive. 46 PTCLs were also evaluated (including 9 AITL). Overall, 8/46 (17%) of the PTCL cases expressed CS-1. However, of the AITLs, 4 of 9 (44%) expressed CS-1. Conclusions: CS-1 is expressed on nearly all nasal type NK/T cell lymphomas and in a substantial proportion of AITLs. These results provide the rationale for exploring elotuzumab in the targeted treatment of NK/T-cell malignancies.

Intraclonal Complexity Of CLL Fractions In Cell Proliferation Rates, Gene Expression Signatures, and Responses To Autologous T-Cell Help In Peripheral blood and Secondary Lymphoid Tissues

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 115-115
Author(s):  
Shih-Shih Chen ◽  
Thomas M. Herndon ◽  
Claire Emson ◽  
John C. Riches ◽  
Fabienne McClanahan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Lymphoid Tissues ◽  
T Cell Help

Abstract Chronic lymphocytic leukemia (CLL) is a disease of resting and dividing B cells. In order to understand the trafficking and transition of proliferative and resting fractions between periphery and lymphoid tissues, we have tried to [1] define the relative levels of CLL B-cell proliferation in distinct anatomic sites, [2] identify and characterize CLL intraclonal fractions from these sites that differ in time since last replication, and [3] model the abilities of these subsets to repopulate immune deficient mice. In the blood, resting and recently-divided CLL cells can be distinguished by surface expression of CXCR4 and CD5. CXCR4dimCD5br (DIM) cells are an activated subset, CXCR4intCD5int (INT) cells are the clonal bulk, and CXCR4brCD5dim (BR) cells are older and more quiescent. Here we compared in vivo proliferation rates, gene expression profiles, and differences in xenografting of these 3 fractions. In addition, we studied the same parameters in 3 other fractions, CXCR4dimCD5dim (dDIM), CXCR4intCD5br (INT/BR) and CXCR4brCD5br (dBR). CLL B-cell kinetics was analyzed in 7 treatment-naïve patients who drank deuterated “heavy” water (2H2O). At day 13, peripheral blood (PB), lymph node (LN), and bone marrow (BM) samples were collected from each patient, and cells from these 3 sites were analyzed for 2H-labeled CD5+CD19+ cells after FACS sorting into 6 fractions: DIM, dDIM, INT, INT/BR, BR and dBR. Overall, more CLL B-cell proliferation was found in LN than PB and BM; only small numbers of divided cells were found in BM. Interestingly, the DIM, dDIM, and INT/BR had the highest 2H-incorporation in LN and PB; and DIM cells from LN and PB showed similar levels of 2H-incorporation. Gene expression profiling using Illumina Human HT12 BeadChips was then performed on the same 6 fractions from PB and LN. Expression value ratios for fractions from each patient were analyzed using R, and sets of significant genes (fold change >1.5 and P<0.05) were determined. Unsupervised hierarchical clustering grouped together the DIM and dDIM fractions from all other fractions. Although the INT/BR had high 2H-incorporation levels, it clustered with the BR, INT and dBR fractions. Genes upregulated in DIM and dDIM included genes involved in cell proliferation and survival, such as DUSP1, PRKCD and BMF, and chemokine genes CCL3, CCL3L1, CCL3L3, CCL4L2. Genes changed in BR, dBR, and INT/BR included negative regulators of cell survival and proliferation, e.g. PRICKLE1 and GRAP. Finally, functional differences in the CLL fractions were analyzed in vivo using NOD/SCID/γcnull (NSG) mice. 3-5x106 PB B cells were injected with 1-1.5x105 resting, autologous T cells. Compared to BR, dBR and INT/BR fractions, DIM and dDIM cells led to more extensive T-cell growth and B-cell expansion in the spleen and BM at week 6. In contrast, INT injected mice exhibited only minimal or no CLL B or T cells. Adding INT cells suppressed DIM and dDIM induced T-cell expansion. This function, which was resistant to irradiation, was associated with greater immunological synapse impairment in vitro. Thus, in vivo kinetics analysis using D2O identified levels of divided cells based on the following ranking: DIM ≥ INT/BR> dDIM > INT> BR=dBR. Although the INT/BR fraction contains recently-divided cells based on 2H-labeling, its genetic signature is similar to fractions containing lesser numbers of recently activated cells, suggesting INT/BR cells have divided but are being inactivated in the microenvironment. Therefore, these cells may represent a transition population between proliferating and resting cells. Because PB and LN DIM fractions are very similar in proliferation rates and gene expression profiles and because little CLL B-cell proliferation occurs in the blood, the circulating DIM fraction accurate reflects LN proliferation. When combining kinetics and gene expression profiling, the DIM and dDIM fractions appear as the most activated intraclonal fractions. In xenografted mice, PB DIM and dDIM cells are better at activating T cells and consequently receiving T-cell help for engraftment and growth. The INT fraction, which constitutes the tumor bulk, inhibits T-cell activation. Finally, the BR and dBR fraction are the older, most quiescent cells in CLL clones. Overall, these results inform about trafficking and transition of CLL cells between lymphoid tissues and periphery, and provide a rationale for preferential therapeutic targeting of these fractions. Disclosures: Riches: Celgene: Research Funding.

Tumor Necrosis Factor-p Gene Expression and Its Relationship to the Clinical Features and Histopathogenesis of Peripheral T-Cell Lymphomas

1994 ◽  
Vol 16 (1-2) ◽  
pp. 125-133 ◽  
Author(s):  
Hirokazu Kato ◽  
Tetsuro Nagasaka ◽  
Atsushi Ichikawa ◽  
Tomohiro Kinoshita ◽  
Takashi Murate ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Clinical Features ◽  
Tumor Necrosis ◽  
P Gene ◽  
T Cell Lymphomas ◽  
Necrosis Factor ◽  
Peripheral T Cell Lymphomas

scholarly journals A Novel Approach for Treatment of T-Cell Malignancies: Targeting T-Cell Receptor Vβ Families

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-29
Author(s):  
Jie Wang ◽  
Katarzyna Urbanska ◽  
Prannda Sharma ◽  
Mathilde Poussin ◽  
Reza Nejati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Cell Receptor ◽  
Brentuximab Vedotin ◽  
T Cell Lymphomas ◽  
T Cell Malignancies

Background: Peripheral T-cell lymphomas (PTCL) encompass a highly heterogeneous group of T-cell malignancies and are generally associated with a poor prognosis. Combination chemotherapy results in consistently poorer outcomes for T-cell lymphomas compared with B-cell lymphomas.1 There is an urgent clinical need to develop novel approaches to treatment of PTCL. While CD19- and CD20-directed immunotherapies have been successful in the treatment of B-cell malignancies, T-cell malignancies lack suitable immunotherapeutic targets. Brentuximab Vedotin, a CD30 antibody-drug conjugate, is not applicable to PTCL subtypes which do not express CD30.2 Broadly targeting pan-T cell markers is predicted to result in extensive T-cell depletion and clinically significant immune deficiency; therefore, a more tumor-specific antigen that primarily targets the malignant T-cell clone is needed. We reasoned that since malignant T cells are clonal and express the same T-cell receptor (TCR) in a given patient, and since the TCR β chain in human α/β TCRs can be grouped into 24 functional Vβ families targetable by monoclonal antibodies, immunotherapeutic targeting of TCR Vβ families would be an attractive strategy for the treatment of T-cell malignancies. Methods: We developed a flexible approach for targeting TCR Vβ families by engineering T cells to express a CD64 chimeric immune receptor (CD64-CIR), comprising a CD3ζ T cell signaling endodomain, CD28 costimulatory domain, and the high-affinity Fc gamma receptor I, CD64. T cells expressing CD64-CIR are predicted to be directed to tumor cells by Vβ-specific monoclonal antibodies that target tumor cell TCR, leading to T cell activation and induction of tumor cell death by T cell-mediated cytotoxicity. Results: This concept was first evaluated in vitro using cell lines. SupT1 T-cell lymphoblasts, which do not express a native functioning TCR, were stably transduced to express a Vβ12+ MART-1 specific TCR, resulting in a Vβ12 TCR expressing target T cell line.3 Vβ family specific cytolysis was confirmed by chromium release assays using co-culture of CD64 CIR transduced T cells with the engineered SupT1-Vβ12 cell line in the presence of Vβ12 monoclonal antibody. Percent specific lysis was calculated as (experimental - spontaneous lysis / maximal - spontaneous lysis) x 100. Controls using no antibody, Vβ8 antibody, and untransduced T cells did not show significant cytolysis (figure A). Next, the Jurkat T cell leukemic cell line, which expresses a native Vβ8 TCR, was used as targets in co-culture. Again, Vβ family target specific cytolysis was achieved in the presence of CD64 CIR T cells and Vβ8, but not Vβ12 control antibody. Having demonstrated Vβ family specific cytolysis in vitro using target T cell lines, we next evaluated TCR Vβ family targeting in vivo. Immunodeficient mice were injected with SupT1-Vβ12 or Jurkat T cells with the appropriate targeting Vβ antibody, and either CD64 CIR T cells or control untransduced T cells. The cell lines were transfected with firefly luciferase and tumor growth was measured by bioluminescence. The CD64 CIR T cells, but not untransduced T cells, in conjunction with the appropriate Vβ antibody, successfully controlled tumor growth (figure B). Our results provide proof-of-concept that TCR Vβ family specific T cell-mediated cytolysis is feasible, and informs the development of novel immunotherapies that target TCR Vβ families in T-cell malignancies. Unlike approaches that target pan-T cell antigens, this approach is not expected to cause substantial immune deficiency and could lead to a significant advance in the treatment of T-cell malignancies including PTCL. References 1. Coiffier B, Brousse N, Peuchmaur M, et al. Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: a prospective study of 361 immunophenotyped patients treated with the LNH-84 regimen. The GELA (Groupe d'Etude des Lymphomes Agressives). Ann Oncol Off J Eur Soc Med Oncol. 1990;1(1):45-50. 2. Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single agent brentuximab vedotin. Blood. 2014;123(20):3095-3100. 3. Hughes MS, Yu YYL, Dudley ME, et al. Transfer of a TCR Gene Derived from a Patient with a Marked Antitumor Response Conveys Highly Active T-Cell Effector Functions. Hum Gene Ther. 2005;16(4):457-472. Figure Disclosures Schuster: Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria.

scholarly journals HOXC4, HOXC5, and HOXC6 Expression in Non-Hodgkin's Lymphoma: Preferential Expression of the HOXC5 Gene in Primary Cutaneous Anaplastic T-Cell and Oro-Gastrointestinal Tract Mucosa-Associated B-Cell Lymphomas

Blood ◽  
1997 ◽  
Vol 90 (10) ◽  
pp. 4116-4125 ◽  
Author(s):  
Janet J. Bijl ◽  
Johan W. van Oostveen ◽  
Jan M.M. Walboomers ◽  
Anja Horstman ◽  
Adriaan J.C. van den Brule ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
B Cell ◽  
Expression Pattern ◽  
Gene Expression Pattern ◽  
Lymphoid Cells ◽  
B Cell Lymphomas ◽  
Preferential Expression ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas

Abstract Most of the 39 members of the homeobox (HOX) gene family are believed to control blood cell development. HOXC4 and HOXC6 gene expression levels increase with differentiation of lymphoid cells. In contrast, HOXC5 is not expressed in the lymphoid lineage, but was found in lymphoid cell lines, representing the neoplastic equivalents of various differentiation stages of T and B lymphocytes. In the present study, we investigated the HOXC4, HOXC5, and HOXC6 gene expression pattern in 89 non-Hodgkin's lymphomas (NHLs) of different histologic subtypes and originating from different sites. Using RNA in situ hybridization and semiquantitative reverse transcription-polymerase chain reaction, we found expression of HOXC4 in 83 of 88 and HOXC6 in 77 of 88 NHLs and leukemias investigated. In contrast, HOXC5 expression was found in only 26 of 87 NHLs and appeared to be preferentially expressed by two specific subsets of lymphomas, ie, primary cutaneous anaplastic T-cell lymphomas (9 of 9) and extranodal marginal zone B-cell lymphomas (maltomas; 7 of 9). These results indicate that, in contrast to HOXC4 and HOXC6, HOXC5 shows a type- and site-restricted expression pattern in both T- and B-cell NHLs.

scholarly journals Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa- associated lymphoid tissue localization

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3785-3791 ◽  
Author(s):  
PC de Bruin ◽  
JA Kummer ◽  
P van der Valk ◽  
P van Heerde ◽  
PM Kluin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Lymphoid Tissue ◽  
Cytotoxic T Cells ◽  
Granzyme B ◽  
Clinical Behavior ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas ◽  
Peripheral T Cell Lymphomas

T-cell non-Hodgkin's lymphomas can be considered the neoplastic equivalents of immunologically functional, site-restricted T lymphocytes. Little is known about the occurrence and clinical behavior of T-cell lymphomas that are the neoplastic equivalents of different functional T-cell subsets. Here, we investigated the prevalence, preferential site, immunophenotype, and clinical behavior of the neoplastic equivalents of activated cytotoxic T cells (CTLs) in a group of 140 nodal and extranodal T-cell lymphomas. Activated CTLs were shown immunohistochemically with a monoclonal antibody against granzyme B, a major constituent of the cytotoxic granules of activated T cells. Granzyme B-positive T-cell lymphomas were mainly found in mucosa- associated lymphoid tissue (MALT; nose, 63% of the cases; gastrointestinal tract, 46%; and lung, 33%). Granzyme B-positive cases with primary localization in MALT were more often associated with angioinvasion (P = .005), necrosis (P = .002), and histologic characteristics of celiac disease in adjacent mucosa not involved with lymphoma. Eosinophilia was more often observed in granzyme B-negative cases (P = .03). Most cases belonged to the pleomorphic medium- and large-cell group of the Kiel classification. CD30 expression was more often found in granzyme B-positive lymphomas of MALT (P = .04), whereas CD56 expression was exclusively found in nasal granzyme B-positive lymphomas. Immunophenotypically, most of the cases should be considered as neoplastic equivalents of activated CTLs based on the presence of T- cell markers on tumor cells. In two cases of nasal lymphoma, tumor cells probably were the neoplastic counterparts of natural killer cells. The prognosis of the granzyme B-positive gastrointestinal T-cell lymphomas was poor but did not differ from granzyme B-negative gastrointestinal T-cell lymphomas. This indicates that, in peripheral T- cell lymphomas, site of origin is more important as a prognostic parameter than derivation of activated CTLs.

scholarly journals Comparison of peripheral T-cell lymphomas and diffuse large B-cell lymphoma

Cancer ◽  
2007 ◽  
Vol 109 (6) ◽  
pp. 1146-1151 ◽  
Author(s):  
Naoto Tomita ◽  
Shigeki Motomura ◽  
Rie Hyo ◽  
Hirotaka Takasaki ◽  
Sachiya Takemura ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
T Cell Lymphomas ◽  
Large B Cell ◽  
Peripheral T Cell Lymphomas

Pathobiology of Peripheral T-cell Lymphomas

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 317-322 ◽  
Author(s):  
Elaine S. Jaffe
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Clinical Features ◽  
Cell Lymphoma ◽  
Systemic Disease ◽  
T Cell Lymphoma ◽  
Adaptive Immune ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

Abstract Peripheral T-cell lymphomas (PTLs) are uncommon, accounting for fewer than 10% of all non-Hodgkin lymphomas. Success in therapy of the PTLs has lagged behind that of aggressive B-cell lymphomas, and most PTLs have a poor prognosis. The molecular pathogenesis of most PTLs is also poorly understood. In the WHO classification, clinical features, in conjunction with morphological and immunophenotypic criteria, are relied on to define most disease entities. Functionally, T-cell lymphomas are related to the two major arms of the immune system, the innate and adaptive immune systems. NK cells and T cells of the innate immune system recognize antigen in the absence of MHC antigens and are involved in mucosal immunity. The lymphomas derived from these cells often involve cutaneous and mucosal sites. The expression of cytotoxic molecules in these lymphomas may predispose to apoptosis by tumor cells and normal bystander cells. Hepatosplenic T-cell lymphoma is a systemic disease derived from functionally immature innate effector cells, most often of γδ T-cell origin. In contrast, most nodal T-cell lymphomas belong to the adaptive immune system. Angioimmunoblastic T-cell lymphoma (AILT) is mostly likely derived from follicular helper T-cells (TFH), a finding that explains many of its pathological and clinical features. Studies of these neoplasms may assist in further unraveling the functional diversity of their normal counterparts.

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