scholarly journals Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T cell development

2020 ◽  
Author(s):  
Yassin Elfaki ◽  
Philippe A. Robert ◽  
Christoph Binz ◽  
Christine S. Falk ◽  
Dunja Bruder ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cell Receptor ◽  
Cell Development ◽  
Thymic Involution ◽  
Double Positive ◽  
Tcr Repertoire ◽  
Thymus Atrophy ◽  
The Impact

ABSTRACTFoxp3+regulatory T (Treg) cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+Foxp3-or CD25-Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.

Loss of Function of the Homeobox Gene Hoxa-9 Perturbs Early T-Cell Development and Induces Apoptosis in Primitive Thymocytes

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 383-393 ◽  
Author(s):  
David J. Izon ◽  
Sofia Rozenfeld ◽  
Stephen T. Fong ◽  
László Kömüves ◽  
Corey Largman ◽  
...  
Keyword(s):  
T Cell ◽  
Hox Genes ◽  
Apoptotic Cell ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Homeobox Gene ◽  
Cell Receptor ◽  
Cell Development ◽  
Loss Of Function ◽  
Double Positive

Abstract Hox homeobox genes play a crucial role in specifying the embryonic body pattern. However, a role for Hox genes in T-cell development has not been explored. The Hoxa-9 gene is expressed in normal adult and fetal thymuses. Fetal thymuses of mice homozygous for an interruption of the Hoxa-9 gene are one eighth normal size and have a 25-fold decrease in the number of primitive thymocytes expressing the interleukin-2 receptor (IL-2R, CD25). Progression to the double positive (CD4+CD8+) stage is dramatically retarded in fetal thymic organ cultures. This aberrant development is associated with decreased amounts of intracellular CD3 and T-cell receptor β (TCRβ) and reduced surface expression of IL-7R and E-cadherin. Mutant thymocytes show a significant increase in apoptotic cell death and premature downregulation of bcl-2 expression. A similar phenotype is seen in primitive thymocytes from adult Hoxa-9−/− mice and from mice transplanted with Hoxa-9−/−marrow. Hoxa-9 appears to play a previously unsuspected role in T-cell ontogeny by modulating cell survival of early thymocytes and by regulating their subsequent differentiation.

scholarly journals VßGene Family Usage in Spontaneous Lymphomas of AKR Mice: Evidence for Defective Clonal Deletion

1992 ◽  
Vol 2 (2) ◽  
pp. 95-101 ◽  
Author(s):  
Cees de Heer ◽  
Bernard de Geus ◽  
Henk-Jan Schuurma ◽  
Henk Van Loveren ◽  
Jan Rozing
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Mesenteric Lymph Nodes ◽  
Double Positive ◽  
Clonal Deletion ◽  
Lymphoma Cells ◽  
Single Positive ◽  
Akr Mice

T-cell receptor (TCR)ß-chain usage and expression of the CD3, CD4, and CD8 differentiation antigens were analyzed in 14 spontaneous AKR lymphomas. Lymphoma cells massively infiltrated and/or proliferated in the organs analyzed (thymus, spleen, and mesenteric lymph nodes), giving rise to a loss of organ structure. One lymphoma occurred only in the thymus, and failed to express CD3, CD4, and CD8. All other lymphomas expressed the CD3/TCR complex. With respect to CD4 and CD8 expression, the lymphomas were either double-negative (DN), double-positive (DP), or single-positive (SP). The frequency of DP (CD4+8+) lymphomas was low compared to the frequency of DP thymocytes in a normal AKR thymus. A substantial heterogeneity was seen in the intensity of CD4 and CD8 expression among various lymphomas, which was independent of the level of CD3 expression. Considering TCR Vßgene family usage, 2 out of 14 lymphomas expressed Vß6. Normally, Vß6+thymocytes are deleted from the thymocyte pool at the immature DP stage of T-cell development in AKR mice. These data support the hypothesis that the lymphocytes in the immature DP stage of T-cell development are susceptible to the induction of AKR lymphomagenesis. The presence of Vß6+lymphoma cells indicates that the lymphomagenesis is accompanied by a defective clonal deletion of cells expressing a possible autoreactive TCR.

scholarly journals Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas

2015 ◽  
Vol 112 (25) ◽  
pp. 7773-7778 ◽  
Author(s):  
Hyung-Ok Lee ◽  
Xiao He ◽  
Jayati Mookerjee-Basu ◽  
Dai Zhongping ◽  
Xiang Hua ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Human T Cell

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell–specific ThPOK transgene (ThPOKconst mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOKconst RAG-deficient mice, which promotes development to the CD4+8+ (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

scholarly journals Stepwise progression of β-selection during T cell development as revealed by histone deacetylation inhibition

2021 ◽  
Author(s):  
Anchi S Chann ◽  
Mirren Charnley ◽  
Lucas Newton ◽  
Andrea Newbold ◽  
Patrick O O Humbert ◽  
...  
Keyword(s):  
T Cell ◽  
Genetic Recombination ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Histone Deacetylation ◽  
Histone Deacetylase 6 ◽  
Functional Connection ◽  
The Impact ◽  
Tcr Signalling

During T cell development, the first step in creating a unique T Cell Receptor (TCR) is the genetic recombination of the TCRβ chain. The quality of this newly recombined gene is assessed at the β-selection checkpoint, and most cells fail this checkpoint and are removed. The coordination of the complex events that combine to control fate at the β-selection checkpoint is not yet understood. We assessed the impact on T cell development of a selective inhibitor to histone deacetylase 6, ACY1215, currently in clinical use. ACY1215 led to bypass of the β-selection checkpoint such that cells in the DN4 stage often lacked expression of TCRβ, and failed to progress to the DP stage. Characterisation of the molecular basis for this bypass revealed a new, pivotal stage in β-selection, the beginning and end of which were defined by the upregulation of the TCR co-receptors, CD28 and CD2 respectively. Within this stage, termed DN3bPre, CD5 and Lef1 are upregulated to reflect pre-TCR signalling. We propose that the progressive expression of CD28, CD5 then CD2 reports and modulates the pre-TCR signal to orchestrate passage through the β-selection checkpoint. By disrupting the functional connection between CD5 and pre-TCR, ACY1215 allows cells to inappropriately bypass the β-selection checkpoint. These findings implicate a refined model of β-selection in which a coordinated increase in expression of pre-TCR, CD5 and Lef1 provides for an escalating test of TCR signalling strength, and culminates in the expression of CD2 to enable exit from the β-selection checkpoint.

scholarly journals Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells

2001 ◽  
Vol 194 (1) ◽  
pp. 99-106 ◽  
Author(s):  
David Allman ◽  
Fredrick G. Karnell ◽  
Jennifer A. Punt ◽  
Sonia Bakkour ◽  
Lanwei Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Surface Proteins ◽  
Lineage Commitment ◽  
Double Positive ◽  
Hematopoietic Stem ◽  
Multipotent Progenitor Cells

Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4+CD8+ double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2−/−) or Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)−/− mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2−/− progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3ε and pre-Tα mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2−/− mice with a TCRβ transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell–specific signals associated with development of DP thymocytes.

Loss of Function of the Homeobox Gene Hoxa-9 Perturbs Early T-Cell Development and Induces Apoptosis in Primitive Thymocytes

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 383-393 ◽  
Author(s):  
David J. Izon ◽  
Sofia Rozenfeld ◽  
Stephen T. Fong ◽  
László Kömüves ◽  
Corey Largman ◽  
...  
Keyword(s):  
T Cell ◽  
Hox Genes ◽  
Apoptotic Cell ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Homeobox Gene ◽  
Cell Receptor ◽  
Cell Development ◽  
Loss Of Function ◽  
Double Positive

Hox homeobox genes play a crucial role in specifying the embryonic body pattern. However, a role for Hox genes in T-cell development has not been explored. The Hoxa-9 gene is expressed in normal adult and fetal thymuses. Fetal thymuses of mice homozygous for an interruption of the Hoxa-9 gene are one eighth normal size and have a 25-fold decrease in the number of primitive thymocytes expressing the interleukin-2 receptor (IL-2R, CD25). Progression to the double positive (CD4+CD8+) stage is dramatically retarded in fetal thymic organ cultures. This aberrant development is associated with decreased amounts of intracellular CD3 and T-cell receptor β (TCRβ) and reduced surface expression of IL-7R and E-cadherin. Mutant thymocytes show a significant increase in apoptotic cell death and premature downregulation of bcl-2 expression. A similar phenotype is seen in primitive thymocytes from adult Hoxa-9−/− mice and from mice transplanted with Hoxa-9−/−marrow. Hoxa-9 appears to play a previously unsuspected role in T-cell ontogeny by modulating cell survival of early thymocytes and by regulating their subsequent differentiation.

scholarly journals Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age

2015 ◽  
Vol 89 (8) ◽  
pp. 4102-4116 ◽  
Author(s):  
Anna Gil ◽  
Maryam B. Yassai ◽  
Yuri N. Naumov ◽  
Liisa K. Selin
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Influenza A Virus ◽  
Influenza A ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Older Individuals ◽  
Cell Responses

ABSTRACTAlterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses to this nonpersistent virus, to which recurrent exposure with new strains is common, changed over time with increasing age. Here, we show a direct correlation between increasing age and narrowing of the HLA-A2-restricted IAV Vα and Vβ T cell repertoires specific to M1 residues 58 to 66 (M158–66), which simultaneously lead to oligoclonal expansions, including the usage of a single identical VA12-JA29 clonotype in all eight older donors. The Vα repertoire of older individuals also had longer CDR3 regions with increased usage of G/A runs, whose molecular flexibility may enhance T cell receptor (TCR) promiscuity. Collectively, these results suggest that CD8 memory T cell responses to nonpersistent viruses like IAV in humans are dynamic, and with aging there is a reduced diversity but a preferential retention of T cell repertoires with features of enhanced cross-reactivity.IMPORTANCEWith increasing age, the immune system undergoes drastic changes, and older individuals have declined resistance to infections. Vaccinations become less effective, and infection with influenza A virus in older individuals is associated with higher morbidity and mortality. Here, we questioned whether T cell responses directed against the highly conserved HLA-A2-restricted M158–66peptide of IAV evolves with increasing age. Specifically, we postulated that CD8 T cell repertoires narrow with recurrent exposure and may thus be less efficient in response to new infections with new strains of IAV. Detailed analyses of the VA and VB TCR repertoires simultaneously showed a direct correlation between increasing age and narrowing of the TCR repertoire. Features of the TCRs indicated potentially enhanced cross-reactivity in all older donors. In summary, T cell repertoire analysis in older individuals may be useful as one of the predictors of protection after vaccination.

scholarly journals T-Cell Tolerance for Variability in an HLA Class I-Presented Influenza A Virus Epitope

2009 ◽  
Vol 83 (18) ◽  
pp. 9206-9214 ◽  
Author(s):  
Angela Wahl ◽  
William McCoy ◽  
Fredda Schafer ◽  
Wilfried Bardet ◽  
Rico Buchli ◽  
...  
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Escape ◽  
Class I ◽  
Immune Recognition ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
The Impact

ABSTRACT To escape immune recognition, viruses acquire amino acid substitutions in class I human leukocyte antigen (HLA)-presented cytotoxic T-lymphocyte (CTL) epitopes. Such viral escape mutations may (i) prevent peptide processing, (ii) diminish class I HLA binding, or (iii) alter T-cell recognition. Because residues 418 to 426 of the hypervariable influenza A virus nucleoprotein (NP418-426) epitope are consistently bound by class I HLA and presented to CTL, we assessed the impact that intraepitope sequence variability has upon T-cell recognition. CTL elicited by intranasal influenza virus infection were tested for their cross-recognition of 20 natural NP418-426 epitope variants. Six of the variant epitopes, of both H1N1 and H3N2 origin, were cross-recognized by CTL while the remaining NP418-426 epitope variants escaped targeting. A pattern emerged whereby variability at position 5 (P5) within the epitope reduced T-cell recognition, changes at P4 or P6 enabled CTL escape, and a mutation at P8 enhanced T-cell recognition. These data demonstrate that substitutions at P4 and/or P6 facilitate influenza virus escape from T-cell recognition and provide a model for the number, nature, and location of viral mutations that influence T-cell cross-recognition.

Dysregulation of T-Cell Development in Adrenal Glucocorticoid-Deprived Rats

2009 ◽  
Vol 234 (9) ◽  
pp. 1067-1074 ◽  
Author(s):  
Zorica Stojić-Vukanić ◽  
Aleksandra Rauški ◽  
Duško Kosec ◽  
Katarina Radojević ◽  
Ivan Pilipović ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Male Rats ◽  
Double Positive ◽  
Cell Repertoire ◽  
Single Positive ◽  
The Impact

A number of different experimental approaches have been used to elucidate the impact of basal levels of adrenal gland-derived glucocorticoids (GCs) on T cell development, and thereby T cell-mediated immune responses. However, the relevance of the adrenal GCs to T cell development is still far from clear. This study was undertaken to explore the relevance of basal levels of GCs to T cell differentiation/maturation. Eight days post-adrenalectomy in adult male rats the thymocyte yield, apoptotic and proliferative rate and the relationship amongst major thymocyte subsets, as defined by TCRαβ/CD4/CD8 expression, were examined using flow cytometry. Adrenal GC deprivation decreased thymocyte apoptosis and altered the kinetics of T cell differentiation/maturation. In the adrenalectomized rats there was increased thymic hypercellularity and an over-representation of the CD4+CD8+ double positive (DP) TCRαβlow cells entering selection, as well as increased numbers of their DP TCRαβ− immediate precursors. These changes were accompanied with under-representation of the postselected DP TCRαβhigh and the most mature CD4−CD8+ and, particularly, CD4+CD8− single positive (SP) TCRαβhigh cells. This data suggests that withdrawal of adrenal GCs produces alterations in the thymocyte selection processes, possibly affecting the diversity of functional T cell repertoire and generation of potentially self-reactive cells as indicated by the reduced proportion and number of CD4−CD8− double negative TCRαβhigh cells. In addition, it indicates that GCs influence the post-selection maturation of thymocytes and plays a regulatory role in controlling the ratio of mature CD4+CD8−/CD4−CD8+ SP TCRαβhigh cells.

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