scholarly journals Peripheral engraftment of fetal intestine into athymic mice sponsors T cell development: direct evidence for thymopoietic function of murine small intestine.

1992 ◽  
Vol 176 (5) ◽  
pp. 1365-1373 ◽  
Author(s):  
R L Mosley ◽  
J R Klein

Adult athymic, lethally irradiated, F1-->parent bone marrow-reconstituted (AT x BM) mice were engrafted bilaterally with day 16-18 fetal intestine or fetal thymus into the kidney capsule and were studied for evidence of peripheral T cell repopulation of 1-12 wk postengraftment. Throughout that time period, both types of grafts were macroscopically and histologically characteristic of differentiated thymus or intestine tissues, respectively. Beginning at week 2 postengraftment, clusters of lymphocytes were present within intestine grafts, particularly in subepithelial regions and in areas below villus crypts. As determined by immunofluorescence staining and flow cytometric analyses, lymphocytes from spleen and lymph nodes of sham-engrafted mice (AT x BM-SHAM) were essentially void of T cells, whereas in AT x BM thymus-engrafted (AT x BM-THG) mice, which served as a positive control for T cell repopulation, normal levels of T cells were present in spleen and lymph nodes by week 3 postengraftment, and at times thereafter. Most striking, however, was the finding that T cell repopulation of the spleen and lymph nodes occurred in AT x BM fetal intestine-engrafted (AT x BM-FIG) mice beginning 3 wk postengraftment. Based on H-2 expression, peripheral T cells in AT x BM-FIG mice were of donor bone marrow origin, and consisted of CD3+, T cell receptor (TCR)-alpha/beta+ T cells with both CD4+8- and CD4-8+ subsets. Peripheral T cells in AT x BM-FIG mice were functionally mature, as demonstrated by their capacity to proliferate after stimulation of CD3 epsilon. Moreover, alloreactive cytotoxic T lymphocytes were generated in primary in vitro cultures of spleen cells from AT x BM-FIG and AT x BM-THG mice, though not in spleen cell cultures from AT x BM-SHAM mice. Histologic studies of engrafted tissues 3-4 wk postengraftment demonstrated that thymus leukemia (Tl) antigens were expressed on epithelial surfaces of intestine grafts, and that both TCR-alpha/beta+ and TCR-gamma/delta+ lymphocytes were present in intestine grafts. Collectively, these findings indicate that the murine small intestine has the capacity to initiate and regulate T cell development from bone marrow precursors, thus providing a mechanism by which extrathymic development of intestine lymphocytes occur.

1988 ◽  
Vol 168 (6) ◽  
pp. 2221-2229 ◽  
Author(s):  
B L Kotzin ◽  
S K Babcock ◽  
L R Herron

The current study examines the possibility that the TCR repertoire of L3T4-, Lyt-2- cells in lpr/lpr mice is enriched for self-reactive specificities. T cells utilizing V beta 17a and V beta 8.1 gene products have been shown to be clonally eliminated in nonautoimmune mice expressing I-Ek and Mlsa/H-2k, respectively, because of their potential self reactivity. We quantitated these V beta specificities in lymph nodes and spleens of lpr/lpr mice. The results indicate that lpr-dependent L3T4-/Lyt-2- T cells, similar to normal peripheral T cells, have undergone a repertoire modification such that potential self-reactive V beta specificities have been eliminated. Evidence for tolerance in this population provides insight into the development of these aberrant cells, and may also have important implications for normal T cell development in the thymus.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Weihong Chen ◽  
Xin Du ◽  
Wenyujing Zhou ◽  
Changru Luo ◽  
Xiaoqing LI

CASE PRESENTATION: A 68-year-old male was diagnosed with CLL/SLL in November 2007. Bone marrow asp/bx: 36.5% lymphocytes, 78% CD19, 65% ATM (11q22 deleted) positive cells, 13.5% D13S25 (13q14.3 deleted). On December 10, 2009, the patient took FCR scheme for five cycles, followed by FR scheme for one cycle, and then a month of Chlorambucil. On September 5, 2013, the patient took BR scheme for four cycles with no effect. From March 2015 to Feb 2016, 420 mg of Ibrutinib was administered daily. On January 15, 2016, the patient developed swollen lymph nodes in his right neck with intermittent lumps, fever and nausea. He was admitted into the hospital at Feb 2, 2016. Test results: multiple swollen superficial lymph nodes over the body, with the biggest measuring 60×30mm on the right neck, with no tenderness. Supplementary tests: peripheral white blood cells (WBC) 11.94×10E9/L, lymphocyte 7.5×10E9/L, CD19 cells 6.73×10E9/L, bone marrow lymphocyte 62%, peripheral blood lymphocyte 52%. Immunophenotype: CD5, CD19, CD20dim, CD23, CD11b dim, HLA-DR expression, visible CD5+CD19+ cell clusters, and visible immunoglobulin cKappa with restricted expression. On March 10, 2016, peripheral blood platelet 60 × 10E9/L, CD19 cells 1.94×10E9/L, lactate dehydrogenase 460U/L, FER 115.6ng/ml, hepatitis B virus carrier. Diagnosis: CLL/SLL IV stage, ATM (11q22) deletion, D13S25 (13q14. 3) positive, CD19 positive. Relapse of CLL/SLL occurred again after four months and at this stage the patient was considered for therapy in a clinical trial of CD19-specific chimeric antigen receptor (CAR-) T cell therapy. Ethical approval and informed consent were obtained for anti-CD19 CAR T Cell treatment of ibrutinib resistance in relapsed/refractory CLL/SLL. We infused autologous T cells transduced with a CAR T 19 retroviral vector with CLL/SLL at doses of 3.3 × 10E8 CART19 cells on Mar. 16 2016. Patients were monitored for responses, toxic effects, and the expansion and persistence of circulating CART19 cells. After CART19 cells were infused, the patient experienced chills, fever, headache, weak, anorexia, nausea, shortness of breath, chest tightness, heart palpitation, hypotension and shock for 9 days. The serum levels of IFN-Υ were at their highest at day 7 after CAR T cells infusion. Serum interleukin 6 (IL-6) was at 680pg/ml and CD3+ cells were 97.5%, CD8+ cells 72.8% (18.7-32.8%), FER was 1529.5ng/ml (Normal No. 22-322ng/ml) 14 days after CAR-T cell infusion. The serum levels of IL-6 were at their highest at day14. The patient was diagnosed as having cytokine release syndrome. After the patient took the anti-IL-6R antibody and anti-TNF antibody, he began to recover gradually. Enlarge lymph nodes shrunk after being infused with CART19 cells for 7 days. The peripheral blood CD19 B lymphocytes were 0 on day 14 after infused with CAR T19 cells. Q-PCR was used to detect the amount of the peripheral blood CART19 cells, which stood at 5485 copies/μl, 924 copies/μl, 191 copies/μl respectively 2 weeks, 6 weeks and 3 months after infusing with CART19 cells. The peripheral blood CART 19 cells were not detectable 4 months after infusing with CART19 cells until present. The lymphadenopathy was decreased gradually after 14 days of infusion. The MRI test showed that lymphadenopathy reduced markedly or disappeared after 6 months of infusion. ATM (11q22 deleted) negative, D13S25 (13q14.3 deleted) negative. After treatment with CAR T 19 cell therapy for 53 months, the patient remained disease-free, the patient's lymph nodes, lymphocytes and I mmunoglobulins were normal. CONCLUSIONS : Cancer immunotherapy as a method of cancer treatment is the most effective after conventional treatments such as radiotherapy, chemotherapy, and surgery. For BTK Inhibitor resistance in relapsed and refractory CD19+ CLL/SLL, CD19 is a favorable target, because the expression of CD19 is limited to B cells and not present in other tissues or cells. Currently, the efficacy of this treatment in treating CLL/SLL remains to be seen. The effects of chemotherapy on the patient's B cell lymphoma are negligible, due to the fact that his CLL/SLL have become relapsed and refractory. As a result we chose the CAR T19 cell therapy genetic engineering technique as a method of treatment, to which the patient has responded well. Therefor, CAR T cell technology overcome the limitations of existing cancer therapies and has great potential for development and application. Disclosures No relevant conflicts of interest to declare.


2009 ◽  
Vol 30 (3) ◽  
pp. 590-600 ◽  
Author(s):  
Wen Qing Li ◽  
Tad Guszczynski ◽  
Julie A. Hixon ◽  
Scott K. Durum

ABSTRACT Interleukin-7 (IL-7) is critical for T-cell development and peripheral T-cell homeostasis. The survival of pro-T cells and mature T cells requires IL-7. The survival function of IL-7 is accomplished partly through induction of the antiapoptotic protein Bcl-2 and inhibition of proapoptotic proteins Bax and Bad. We show here that the proapoptotic protein Bim, a BH3-only protein belonging to the Bcl-2 family, also plays a role in peripheral T-cell survival. Deletion of Bim partially protected an IL-7-dependent T-cell line and peripheral T cells, especially cells with an effector memory phenotype, from IL-7 deprivation. However, T-cell development in the thymus was not restored in IL-7−/− Rag2−/− mice reconstituted with Bim−/− bone marrow. IL-7 withdrawal altered neither the intracellular location of Bim, which was constitutively mitochondrial, nor its association with Bcl-2; however, a reduction in its association with the prosurvival protein Mcl-1 was observed. IL-7 withdrawal did not increase Bim mRNA or protein expression but did induce changes in the isoelectric point of BimEL and its reactivity with an antiphosphoserine antibody. Our findings suggest that the maintenance of peripheral T cells by IL-7 occurs partly through inhibition of Bim activity at the posttranslational level.


1973 ◽  
Vol 138 (5) ◽  
pp. 1044-1055 ◽  
Author(s):  
F. Loor ◽  
B. Kindred

When the thymus from an AKR mouse (TL-, θ-AKR) is grafted to a BALB/c-nu/nu mouse (TL2, θ-C3H), the grafted thymus is rapidly repopulated by host lymphocytes, i.e., lymphocytes having the TL2 and θ-C3H T-lymphocyte membrane antigen markers. θ-C3H lymphocytes also appear rapidly in the spleen and lymph nodes. After a few weeks, BALB/c nude mice grafted with AKR thymus and normal BALB/c mice could not be distinguished on the basis of the number of TL-positive thymocytes or θ-C3H-positive lymphocytes in thymus, spleen, or lymph nodes. These experiments give a definitive proof of the existence of precursor cells for the T compartment of the lymphoid system in the nude mouse. They strongly suggest the involvement of host-derived T cells in the recovery of some T-cell functions by nude mice grafted with allogeneic thymuses.


1993 ◽  
Vol 177 (4) ◽  
pp. 1153-1164 ◽  
Author(s):  
A Bonomo ◽  
P Matzinger

Most current models of T cell development include a positive selection step in the thymus that occurs when T cells interact with thymic epithelium and a negative selection step after encounters with bone marrow-derived cells. We show here that developing T cells are tolerized when they recognize antigens expressed by thymic epithelium, that the tolerance is tissue specific, and that it can occur by deletion of the reactive T cells.


1994 ◽  
Vol 14 (3) ◽  
pp. 1566-1574 ◽  
Author(s):  
J Jain ◽  
E A Nalefski ◽  
P G McCaffrey ◽  
R S Johnson ◽  
B M Spiegelman ◽  
...  

The ubiquitous transcription factors Fos and Jun are rapidly induced in T cells stimulated through the T-cell antigen receptor and regulate transcription of cytokines, including interleukin 2, in activated T cells. Since positive and negative selection of thymocytes during T-cell development also depends on activation through the T-cell receptor, Fos and Jun may play a role in thymocyte development as well. Fos and Jun act at several regulatory elements in the interleukin 2 promoter, including the AP-1 and NFAT sites. Using antisera specific to individual Fos and Jun family members, we show that c-Fos as well as other Fos family members are present in the inducible AP-1 and NFAT complexes of activated murine T cells. Nevertheless, c-Fos is not absolutely required for the development or function of peripheral T cells, as shown by using mice in which both copies of the c-fos gene were disrupted by targeted mutagenesis. c-Fos-deficient mice were comparable to wild-type mice in their patterns of thymocyte development and in the ability of their peripheral T cells to proliferate and produce several cytokines in response to T-cell receptor stimulation. Our results suggest that other Fos family members may be capable of substituting functionally for c-Fos during T-cell development and cytokine gene transcription in activated T cells.


2018 ◽  
Author(s):  
G. Sugiyarto ◽  
D. Prossor ◽  
O. Dadas ◽  
T. Elliott ◽  
E. James

AbstractRegulatory T cells (Treg) play a major role in the suppression of protective anti-tumour T cell responses. In the CT26 BALB/c murine model of colorectal carcinoma, Tregs differentially suppress responses to two characterised CD8+ T epitopes, AH1 and GSW11, which results in an absence of detectable IFN-γ producing GSW11- specific T cells in the spleen and lymph nodes of tumour challenged mice. Activation of GSW11-specific T cells correlates with protection against tumour growth. Here we show that GSW11-specific T cells are in fact induced in Treg-replete, CT26-bearing mice, where they make up the majority of tumour infiltrating CD8+ lymphocytes, but exhibit a dysfunctional ‘exhausted’ phenotype. This dysfunctional phenotype is induced early in the anti-tumour response in draining lymph nodes, spleens and tumours and is significantly more pronounced in GSW11-specific T cells compared to other tumour-specific T cell responses. Depletion of Tregs prior to tumour challenge significantly reduces the induction of exhaustion in GSW11-specific T cells and correlates with altered T cell receptor (TcR) usage. Moreover, the avidity of GSW11- specific TcRs that expanded in the absence of Tregs was significantly lower compared to TcRs of cytotoxic T lymphocyte (CTL) populations that were diminished in protective anti-tumour responses. This indicates that Tregs suppress the induction of protective anti-tumour T cell responses and may signify that the induction of low avidity T cells, while being more susceptible to exhaustion are the most efficacious in tumour rejection.


Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3984-3992 ◽  
Author(s):  
E Roux ◽  
C Helg ◽  
F Dumont-Girard ◽  
B Chapuis ◽  
M Jeannet ◽  
...  

We have studied the repopulation of the T-cell compartment in 27 patients transplanted with bone marrow from an (HLA)-identical sibling. Significant differences were found between recipients of unmanipulated and T-cell depleted grafts. Analysis of the T cells by a method based on amplification of minisatellite DNA regions showed that without depletion > 99.9% of the clones responding to a mitogenic stimulus after transplantation were of donor origin. In contrast, when the graft had been depleted with Campath-1M plus complement, a significant part of the T cells cloned during the first weeks after transplantation comprised of recipient T cells that had survived the preconditioning. This mixed population of low numbers donor and recipient T cells (19 +/- 31/mm3 at day 14) expanded rapidly (predominantly CD8+ T cells) during the first 2 months, without a significant change of the ratio of recipient/donor T cells. In 11 of 17 evaluable patients a late wave ( > 9 months) of donor T cells occurred. As a consequence, T-cell chimerism changed in favor of donor T cells and the CD4/CD8 ratio that had been reversed ( < 0.5) after the first expansion, normalized (1.5 +/- 0.51). Analysis of the T-cell receptor repertoire showed that in recipients of a T-cell depleted graft, the recipient as well as the donor T cells that repopulated the peripheral T-cell pool during the first month, were the progeny of a limited number of precursors. Because without depletion, when larger numbers of donor T cells had been cotransfused with the marrow, the repertoire was much more diverse, these data show that immediately after transplantation, the peripheral pool is repopulated primarily through expansion of circulating T cells.


Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4755-4764 ◽  
Author(s):  
S. Önder Alpdogan ◽  
Sydney X. Lu ◽  
Neel Patel ◽  
Suzanne McGoldrick ◽  
David Suh ◽  
...  

Abstract Delayed T-cell recovery is an important complication of allogeneic bone marrow transplantation (BMT). We demonstrate in murine models that donor BM-derived T cells display increased apoptosis in recipients of allogeneic BMT with or without GVHD. Although this apoptosis was associated with a loss of Bcl-2 and Bcl-XL expression, allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)- or Bax-, or BM-overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor-derived T cells. CD44 expression was associated with an increased percentage of BM-derived apoptotic CD4+ and CD8+ T cells. Transplantation of RAG-2-eGFP–transgenic BM revealed that proliferating eGFPloCD44hi donor BM-derived mature T cells were more likely to undergo to apoptosis than nondivided eGFPhiCD44lo recent thymic emigrants in the periphery. Finally, experiments using carboxyfluorescein succinimidyl ester–labeled T cells adoptively transferred into irradiated syngeneic hosts revealed that rapid spontaneous proliferation (as opposed to slow homeostatic proliferation) and acquisition of a CD44hi phenotype was associated with increased apoptosis in T cells. We conclude that apoptosis of newly generated donor-derived peripheral T cells after an allogeneic BMT contributes to delayed T-cell reconstitution and is associated with CD44 expression and rapid spontaneous proliferation by donor BM-derived T cells.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4477-4477
Author(s):  
Kaifeng Lisa Lin ◽  
LeShara M Fulton ◽  
Jonathan Serody

The transcription factor aryl hydrocarbon receptor (AhR) is a cytosolic sensor of numerous small synthetic compounds (xenobiotics) and natural chemicals. Ligand binding of AhR causes a conformational change of the receptor, allowing its translocation to nucleus to regulate an array of genes. Different ligands could induce different sets of genes. AhR was first discovered as the mediator of dioxin toxicity. Its role in immunity was recently extensively investigated and expanded exponentially. Here we investigated the role of AhR in donor T cell-induced graft-versus-host diseases (GvHD) after bone marrow transplant in two MHC-mismatched models. B6D2 or Balb/c recipients were irradiated with one dose (950 rads for B6D2 and 800 rads for Balb/c) one day before transplant. C57BL/6 WT or AhR deficient (AhR KO) T cells were transplanted with T cell-depleted bone marrow to B6D2 or Balb/c, at a dose of three million T cells or five hundred thousand T cells, respectively. At different time points, recipient lymphoid organs or target organs were harvested and used for flow analysis or ELISA. A group of recipient mice were observed for an extended time to establish GvHD scores and survival curves. In B6 to B6D2 model, recipient mice transplanted with AhR KO T cells displayed lower GvHD scores and survived longer than mice transplanted with WT T cells (Figure 1C). We found that AhR KO donor T cells failed to accumulate in lymph nodes and spleen as rapidly as WT T cells as evident on day 1 and day 3 post-transplant (Figure 1A). Further investigation showed that the proliferation and cell death were similar between WT and AhR donor T cells, suggesting decreased migration of AhR KO T cells to lymphoid organs. It has been shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced AhR activation leads to the up-regulation of CCR4 and CCR5 in T cells, supporting our data that AhR affects cell migration. We also observed that lower percentage of AhR KO T cells produced IFN-g and IL-17 in lymph nodes and spleen early after transplant, but the differences disappeared at later time points (day 7). Colonic homogenates of AhR KO transplants contained less IFN-g, TNF-a, and IL-1a than WT transplants, which indicated that AhR KO T cells caused less inflammation in the gut (Figure 1B). Gut-associated injury due to inflammation is the major cause of death in this model. However, in B6 to Balb/c model, recipient mice transplanted with AhR KO T cells displayed the opposite survival curve. They had diminished survival compared to mice receiving WT T cells with most mice succumbing to GvHD around day 10 to day 15 before the onset of diarrhea. AhR KO T cells in this model still accumulated less in lymph nodes at early time points, which suggested that AhR played a role in cell migration in both models. It was noteworthy that after day 6, the number of AhR KO T cells in the spleen was actually similar to or higher than WT T cells in both models, suggesting cell proliferation was not affected by AhR deficiency. In conclusion, AhR KO T cells demonstrate decreased migration to lymphoid organs after bone marrow transplant compared to WT T cells. This decrease in migration may be the reason why mice transplanted with AhR KO T cells exhibit less inflammation in the gut and subsequently survive better from GvHD in the B6 to B6D2 model. However, mice transplanted with AhR KO T cells have diminished survival in B6 to Balb/c model despite of lower T cell numbers in lymph nodes at early time points. Thus, certain function of AhR in donor T cells is model dependent while other function is conserved among different models. These data suggest that investigators should be cautious regarding the supplementation of AhR ligands to diminish GvHD in clinical studies. Disclosures: No relevant conflicts of interest to declare.


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