A Beginner's Guide to T Cell Development.

T lymphocytes (T cells) are essential components of the adaptive immune system; they serve multiple functions in responses to pathogens and to ensure immune homeostasis. Written for readers first entering this field of study, this chapter is a brief overview of the development of T cells in the thymus, from the entry of thymus-settling bone marrow-derived precursors to the egress of mature T cells. Surveyed topics include the differentiation and expansion of early precursors, the generation of the T cell antigen receptor repertoire, the selection of αß T cell precursors, and their acquisition of functional competency.

Reactive Langerhans Cell Proliferation Mimicking Langerhans Cell Histiocytosis in Association with Sézary Syndrome: A Case Report and Literature Review.

Sézary syndrome (SS) is a rare type of cutaneous T-cell lymphoma (CTCL) that is characterized by erythroderma, lymphadenopathy and circulating clonal T-cells (Sézary cells). However, to our knowledge, reactive Langerhans cell (LC) proliferation mimicking Langerhans cell histiocytosis (LCH) associated with SS has not been reported. In this report, we describe an unusual case of reactive LC proliferation mimicking LCH associated with SS in a 57-year-old female patient. With complaints of recurrent skin symptoms and enlarged lymph nodes (LNs), she was admitted to our center with a presumptive diagnosis of LCH as demonstrated by LN biopsy pathology. However, other than adenopathy, no lesions were noted in any organ system commonly involved in LCH. Typical Sézary cells were identified through morphology and further confirmed by flow cytometric immunophenotyping in peripheral blood (PB) and bone marrow (BM). In addition, T-cell receptor gene rearrangement was positive, whereas the BRAF V600E gene mutation was negative in skin, LN, PB and BM. The patient was ultimately diagnosed with SS with reactive LC proliferation. This case should remind clinicians to be wary of diagnosing LCH if LCH-like pathology occurs exclusively in LNs. Moreover, morphologic, immunologic, cytogenetic and molecular biologic studies should be performed to avoid misdiagnosis.

CD3-CD4+ Lymphocytic Variant Hypereosinophilic Syndrome: Diagnostic Tools Revisited.

BACKGROUND: Identification of patients with lymphocytic variant hypereosinophilic syndrome (L-HES) is challenging, and has important prognostic and therapeutic implications. OBJECTIVE: This study was undertaken to assess diagnostic tools for L-HES and to develop evidence-based diagnostic recommendations. METHODS: Biomarkers of T-cell-driven disease were compared between patients with L-HES versus idiopathic HES (I-HES) variants. Those performed routinely (serum immunoglobulin levels, T-cell phenotyping, T-cell receptor [TCR] gene rearrangement patterns) were collected from medical files, whereas others were prospectively assessed on stored blood samples (serum CCL17/thymus and activation regulated chemokine [TARC] levels, in vitro cytokine production). RESULTS: This study included 48 patients with I-HES and 20 with L-HES associated with a CD3-CD4+ T-cell subset, including 7 with less than 5% aberrant cells. Neither increased serum immunoglobulin levels nor clonal TCR gene rearrangements were sufficiently sensitive or specific for L-HES. In contrast, systematically enhanced expression of the T-cell surface antigens CD2, CD5, CD45RO, and CD95 by these cells allowed for accurate detection by flow cytometry. Serum CCL17/TARC levels were significantly higher in patients with L-HES compared with those with I-HES, and a threshold of 3000 pg/mL allowed for detection of all subjects with L-HES with 75% specificity. Quantification of intracytoplasmic cytokine production by flow cytometry is the most reliable method for detection of enhanced type 2 cytokine expression, most notably for IL-4 and IL-13. CONCLUSION: Adapting the standard of procedure for T-cell phenotyping in patients with unexplained hypereosinophilia is currently the most reliable means of identifying those with CD3-CD4+ L-HES.

The application of antigen receptor gene rearrangement of BIOMED-2 in the pathologic diagnosis of 348 cases with non-Hodgkin lymphoma in a single institution in Southwest of China.

OBJECTIVE: To explore the clinical value of immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangement in the diagnosis of non-Hodgkin lymphoma. METHODS: Using the standardized BIOMED-2 multiplex PCR strategy to detect IgH, IgK and TCR in 272 cases of mature B-cell lymphoma, 55 cases of mature T-cell lymphoma, 21 cases of extranodal NK/ T-cell lymphoma, nasal type, and 20 cases of lymphoid tissue reactive hyperplasia. RESULTS: Among all mature B-cell lymphomas, the sensitivity of Ig gene rearrangement was 91.18% (248/272), IgH and IgK gene rearrangement was 76.47% (208/272) and 75.00% (204/272), respectively, meanwhile the sensitivity of TCRγ rearrangement was 3.68% (10/272). In the 55 cases of mature T-cell lymphoma, the sensitivity of the detection of TCRγ was 76.36% (44/55), at the same time the sensitivity of Ig gene rearrangement was 14.55% (8/55), IgH and IgK gene rearrangement was 7.27% (4/55) and 12.73% (7/55), respectively. In 21 cases of extranodal NK/T cell lymphoma, nasal type, and 20 cases of reactive lymphoid hyperplasia, no gene rearrangement was found in the samples of IgH, IgK and TCR. The sensitivity of gene rearrangement in Ig/TCR in B and T-cell lymphoma was significantly different from that in the control group (P < 0.05). CONCLUSION: The Ig/TCR gene rearrangement of BIOMED-2 multiplex PCR strategy has important auxiliary value in the diagnosis of B/T-cell non-Hodgkin lymphoma respectively, however, a few B-cell lymphomas may company TCR gene rearrangement as well as a few T-cell lymphomas may accompany Ig gene rearrangement, it must be comprehensively judged with the combination of morphology, immunohistochemistry and clinical features.

Minimal residual disease (MRD) detection using rearrangement of immunoglobulin/T cell receptor genes in adult patients with acute lymphoblastic leukemia (ALL).

MRD detection with allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR) and using clone-specific immunoglobulin/T cell receptor rearrangements is considered as a powerful prognostic factor in acute lymphoblastic leukemia (ALL). In the present study, we evaluated an ASO-qPCR assay for MRD quantification in peripheral blood (PB) samples of adult patients with ALL. DNA was isolated from PB samples of patients with newly diagnosed ALL. They were first investigated by multiplex-PCR assay to identify V/J usage. An ASO-qPCR technique was then applied for 2.5-year monthly MRD quantification for detection of patient-specific Ig/TCR receptor rearrangements as a molecular target. From 98 patients who were diagnosed as ALL, 72 (73.5%) were enrolled in the present study for MRD detection. MRD was successfully quantified in patients with 1-month interval time. MRD level at the end of induction therapy up to day 88 was the only significant prognostic factor. Regarding MRD level, patients were categorized into two groups of low and high-risk. 2.5-year OS in all three time points (days 28, 58 and 88) were significantly lower in high-risk group (P < 0.008). The results of the 2.5-year MRD detection indicate that MRD level at the end of induction up to about 6 months after the first diagnosis was associated with clinical outcome. This study may highlight the usefulness of PB and the definitions of cut-off level for early prediction of relapse and for stratifying ALL patients. Short-interval time points and frequent PB sampling to monitor MRD level is suggested for early clinical relapse prediction and clinical management of the disease.

Clonality testing of lymphoproliferative disorders in a large cohort of primary and consultant biopsies.

BACKGROUND: Lymphoproliferative disease often presents the clinician and pathologist with a diagnostic dilemma, particularly in the early course of the disease. METHODS: We used modified BIOMED-2 protocols to detect monoclonal expansions of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) genes in 957 formalin-fixed paraffin-embedded samples from 717 patients. To eliminate false-positive results, heteroduplex analysis was used after PCR reactions. The impact of different fixatives on DNA quality and performance of PCR was assessed. RESULTS: In the class of B lymphomas we detected clonal IgH rearrangement in nearly 80% of cases and in the class of T lymphomas in 64% of cases. Performance of the assays was 94.7% and 92.5% for IgH and TCR clonality, respectively. Clonality rates in various B and T lymphomas were in concordance with previous studies. We also present 10 difficult cases where PCR analysis of IgH and TCR gene rearrangements significantly contributed to a decision on the correct diagnosis. CONCLUSION: These results confirm that the PCR-based analysis is suitable as a routine method and is helpful in establishing a diagnosis in morphologically unclear cases.

Extranodal natural killer/T-cell lymphoma, nasal type in Taiwan: a relatively higher frequency of T-cell lineage and poor survival for extranasal tumors.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a predominantly extranodal lymphoma associated with Epstein-Barr virus occurring most frequently in the upper aerodigestive tract. There are limited reports on cellular origin and prognostic factors. We retrospectively investigated 73 cases with a median age of 54 years and a male-female ratio of 2.0:1. The upper aerodigestive tract (nasal group) was the most common site of involvement (51 cases; 70%). The other organs (n = 22; extranasal group) included the skin (12 cases; 16%) and gastrointestinal tract (5; 7%). Of the 70 cases with complete staging, 71% had stage I/II disease. All cases were positive for Epstein-Barr virus by in situ hybridization. Using immunohistochemistry and clonality assay for T-cell receptor gene rearrangement, these tumors were classified into NK (n = 39; 53%), T (n = 13; 18%), and indeterminate lineage (n = 21; 29%). The only clinicopathological difference among these 3 groups was rare CD5 expression in the NK-cell group. Nasal tumors were more frequently of NK-cell origin, and extranasal tumors were equally of either T- or NK-cell origin. The 5-year overall survival rate was 35.6%. The overall survival time was shorter in the extranasal group, although there was no statistical difference in age, sex, and histologic or immunophenotypic features between the 2 groups. Excluding the cases with indeterminate lineage, 75% of cases were of NK lineage; and 25%, T lineage. Extranasal tumors were more aggressive than their nasal counterparts. A prospective national study is warranted for a better understanding of the clinicopathological and genetic features of this uncommon tumor and the prognostic factors.

Primary central nervous system extranodal NK/T cell lymphoma, nasal type, with antecedent hemophagocytic syndrome in a child.

Primary central nervous system (CNS) extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is an exceedingly uncommon entity. Here, we present a case of CNS NKTCL that manifested initially as hemophagocytic syndrome 4 months earlier in a 13-year-old girl. Histological examination revealed the cerebellum mass was composed of large-sized and atypical tumor cells, with an angiocentric and angiodestructive growth pattern and prominent necrosis. The tumor cells exhibited marked pleomorphism with conspicuous nucleoli and prominent mitotic activity. Immunohistochemical staining showed the tumor cells were positive for CD45, CD2, CD3ε, CD30, CD43, CD56, and granzyme B. Epstein-Barr virus--encoded ribonucleic acid was expressed in almost all of the nuclei of the lymphoma cells. The T-cell receptor γ chain gene rearrangement study showed no evidence of a clonal rearrangement. The patient was treated with etoposide and dexamethasone and died a few days after the operation. As far as we know, this case is the 1st pediatric and female patient of primary CNS NKTCL with antecedent hemophagocytic syndrome, which highlights the clinical data and is helpful for the diagnosis of this tumor.

A Case of Hepatosplenic T-cell Lymphoma Diagnosed by Bone Marrow Examination

Hepatosplenic T-cell lymphoma (HSTL) is a condition in which lymphoma cells infiltrate the sinusoids of the liver, spleen, and bone marrow, without lymph node involvement. We encountered a case of hepatosplenic T-cell lymphoma in a Vietnamese woman. The patient was hospitalized with epigastric pain and nausea. Splenomegaly and multiple poorly defined, low-attenuating nodular lesions in the liver were visualized on computed tomography (CT), and thrombocytopenia was noted. The lymph nodes were not significantly enlarged. Splenic biopsy could not be performed because of severe thrombocytopenia. Neoplastic lymphoid cells were present in bone marrow aspirates. Bone marrow sections revealed infiltration of CD3(+) and CD20(-) neoplastic lymphoid cells in the sinusoids. A clonality assay (IdentiClone T-Cell Receptor Delta Gene Clonality Assay; Invivoscribe Technologies, USA) showed gene rearrangements in the T-cell receptor delta gene. Thus, we made a confirmatory diagnosis of HSTL. When splenic biopsy is not available, bone marrow aspirates and clonality assessment may become useful diagnostic tools.

A Case of CD7+, CD4-, CD8-, CD3-acute T cell lymphoblastic leukemia / 대한임상병리학회지

A CD7 positive acute leukemia, lacking CD4, CD8, CD3, CD13 and CD33 expression may include 4 categories; acute T-cell leukemia, mixed lineage leukemia, acute undifferentiated leukemia and CD7 positive acute myeloid leukemia. Therefore, the expression of cyCD3 or the presence of TCR gene rearrangement can make the diagnosis of acute T-cell leukemia. We report a patient with acute T-cell lymphoblastic leukemia, showing CD7+, CD4-CD8-, and CD3-expression and TCR gamma gene rearrangement.

Alteration of configuration of immunoglobulin and T cell receptor genes in early stage of children acute leukemia / 中国免疫学杂志

Phenotypic markers of leukemic cells from 29 children with acute leukemia were examined. Of these cases, six were negative for myeloperoxidase and did not react with lineage-associated or mature lineage-associated monoclonal antibodies. Then, we analyzed the configuration of both immunoglobulin (heavy chain and kappa chain) and T-cell receptor (?, ?, ?) genes in these six cases. All cases had rearrangement of IgH were suggestive of B-lymphoid origin of these leukemic cells. Two cases without CD10 antigen had no rearrangement of kappa chain, one with retention of the germline configuration of TCR ?, ?. ?, the other with retention of the germline of TCR ? gene. In the cases with CD10 antigen, two cases showed kappa chain deletion, the alteration of TCR genes (rearrangements or deletions )was shown to occur frequently. These findings may implicate that the gene rearrange ments forming functional IgH gene in leukemic cells with CD10 antigen, induce the alteration of IgL and TCR genes.