Generation of primary antigen-specific human cytotoxic T lymphocytes in human/mouse radiation chimera

Blood ◽  
1996 ◽  
Vol 88 (2) ◽  
pp. 721-730 ◽  
Author(s):  
H Segall ◽  
I Lubin ◽  
H Marcus ◽  
A Canaan ◽  
Y Reisner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Lymphocytes ◽  
Scid Mice ◽  
Human Antibody ◽  
Adoptive Therapy ◽  
Activation Markers ◽  
Human T Cell ◽  
Human T Cells

Severe combined immunodeficient (SCID) mice are increasingly used as hosts for the adoptive transfer of human lymphocytes. Human antibody responses can be obtained in these xenogeneic chimeras, but information about the functionality of the human T cells in SCID mice is limited and controversial. Studies using human peripheral blood lymphocytes (PBL) injected intraperitoneally (IP) into SCID mice (hu-PBL-SCID mice) have shown that human T cells from these chimeras are anergic and have a defective signaling via the T-cell receptor. In addition, their antigenic repertoire is limited to xenoreactive clones. In the present study, we tested the functionality of human T cell in a recently described chimeric model. In this system, BALB/c mice are conditioned by irradiation and then transplanted with SCID bone marrow, followed by IP injection of human PBL. Our experiments demonstrated that human T cells, recovered from these hu-PBL-BALB mice within 1 month posttransplant, proliferated and expressed activation markers upon stimulation with anti-CD3 monoclonal antibody. A vigorous antiallogeneic human cytotoxic T-lymphocyte (CTL) response could be generated in these mice by immunizing them with irradiated allogeneic cells. Moreover, anti-human immunodeficiency virus type 1 (HIV-1) Net- specific human CTLs could be generated in vivo from naive lymphocytes by immunization of mouse-human chimeras with a recombinant vaccinia-nef virus. This model may be used to evaluate potential immunomodulatory drugs or cytokines, and could provide a relevant model for testing HIV vaccines, for production of antiviral T-cell clones for adoptive therapy, and for studying human T-cell responses in vivo.

scholarly journals Immunohistology and immunocytology of human T-cell chimerism and graft- versus-host disease in SCID mice

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3440-3448 ◽  
Author(s):  
G Hoffmann-Fezer ◽  
C Gall ◽  
U Zengerle ◽  
B Kranz ◽  
S Thierfelder
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Graft Versus Host Disease ◽  
Scid Mice ◽  
White Pulp ◽  
Activation Markers ◽  
Host Disease ◽  
Graft Versus Host ◽  
Human T Cell

Abstract Surprisingly little graft-versus-host disease (GVHD) has been observed in severe combined immunodeficient (SCID) mice injected intraperitoneally (IP) with human blood lymphocytes (hu-PBL-SCID), which raised the question as to whether GVHD in such a distant species is sporadic or suppressed because of immunologic reasons. After screening for blood T-cell chimerism, we hereby describe generalized lethal xenogeneic human GVHD in unconditioned SCID chimeras, which resembles GVHD in SCID mice injected with allogeneic lymphocytes. We adapted an immunocytochemical slide method for minute cell numbers, which allowed us to follow, by multimarker phenotyping of weekly mouse- tail bleeds, the chimeric status of 100 hu-PBL-SCID injected with 10(7) or 10(8) hu-PBL of Epstein-Barr virus- (EBV-) donors. More than half of the mice showed no or less than 2% T cells. However, 13% to 21% developed substantial blood T-lymphocyte chimerism (10% to 80% human CD+ cells) and high mortality. Immunohistology showed more human CD8+ than CD4+ T cells in the splenic white pulp. The cells developed HLA-DR activation markers and infiltrated the red pulp where human B cells also appeared. Expression of activation and proliferation markers increased within 5 to 6 weeks. Many human CD3+ cells were also found in the portal triads of the liver and in the lung, pancreas, and kidney. The thymus also became heavily infiltrated. The intestines and skin of hu-PBL-SCID were less infiltrated by donor cells than in SCID with allogeneic GVHD. The tongue contained almost no human T cells. Our data show that a relatively low overall incidence of human xenogeneic GVHD, even when high numbers of human PBL are injected, is the consequence of a dichotomy between mice with no or transient T-cell chimerism and a minority of mice with high-blood T-lymphocyte chimerism and GVHD mortality.

Naive and Ex Vivo Activated Human T Cells Generate Consistent Engraftment and Lethal Graft-Versus-Host Disease (GvHD) in NOD SCID β 2M Null Mice: A New Xenogeneic Model for GvHD.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3106-3106
Author(s):  
Bruno Nervi ◽  
Michael P. Rettig ◽  
Julie K. Ritchey ◽  
Gerhard Bauer ◽  
Jon Walker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Conditioning Regimen ◽  
Activation Markers ◽  
In Vivo Models ◽  
Hematopoietic Stem ◽  
Human T Cells ◽  
The Impact

Abstract GvHD remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion. The human GvHD pathophysiology includes recipient tissue destruction and proinflammatory cytokine production associated with the conditioning regimen; donor T cells become allo-activated, proliferate, and mediate tissue injury in various organs, including the liver, skin, and gut. Modern therapeutic strategies to control GvHD while maintaining the beneficial graft-versus-leukemia effects require ex vivo T cell stimulation and expansion. Multiple studies have demonstrated that these ex vivo expanded T cells exhibit decreased survival and function in vivo, including reduced alloreactivity and GvHD potential. Unfortunately no in vivo models exist to consistently examine the impact of ex vivo manipulation of human T cells (HuT) on T cell function. Naive HuT were compared to HuT activated using CD3/28 beads (XcyteTMDynabeads) with 50 U/ml IL-2 for 4 days (Act). We initially evaluated the HuT engraftment and GvHD potential of naive and Act in RAG2γ null mice (n=22) conditioned with clodronate liposomes on day −1 and 350cGy on day 0, as previously described by others. We injected 107 and 1.5x107 naive or Act HuT intravenously (iv). All mice exhibited low HuT engraftment and no lethal GvHD. NOD SCIDβ 2M null mice (β 2M) were next conditioned with 250cGy on day −1 (n=34), or 300cGy on day 0 (n=21). 107 naive vs Act HuT were injected retroorbitaly (ro). Lower HuT doses or iv injection resulted in no expansion or GvHD. Engraftment of HuT in peripheral blood of recipient mice was evaluated weekly by FACS and euthanasia was performed if mice lost > 20% body weight. 60% of the mice conditioned with 250cGy that received naive HuT developed lethal GvHD, in comparison to 75% of mice that received 300cGy and nave HuT, and 100% of mice that received 300cGy and Act HuT. Table 1 250cGy 300cGy Naive (n=34) Naive (n=8) Activated (n=13) *p<0.02 PB engraftment (%HuT) 20%±15 33%±21 59%±19 Lethal GvHD 60% 75% 100% All mice receiving 300cGy had well preserved CD4/CD8 ratios (1–1.5). Tissue infiltration was greatest in mice that had received 300cGy and Act HuT (spleen, liver, lung, kidney: 50–70%). Of interest, serum levels of hu IFNγ dramatically increased over time in all mice who went on to develop lethal GvHD (day 3=270 ug/ml and day 15=36,000 ug/ml) compared to mice that did not develop lethal GvHD (day 10=40 ug/ml and day 17=1,020 ug/ml)(p<0.05). Interestingly, the up-regulation of the activation markers CD25 and CD30 in HuT, and IFNγ production predicted lethal GvHD in β 2M null mice. In summary, we developed a xenogeneic model of lethal GvHD where naive or ex vivo Act HuT injected ro in sublethaly irradiated β 2M not only engraft, expand in vivo, but also infiltrate and damage different mouse target organs. HuT are allo-activated against mouse antigens and damage the target tissues, sharing the major characteristics of human GvHD and causing the death of mice. This model will allow us to study the effects of specific ex vivo T cell manipulation including transduction, selection, expansion, and the depletion or addition of various T cells and other cellular subsets on the outcome of GvHD, to determine improved therapeutic interventions.

CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 696-706 ◽  
Author(s):  
De-Gang Song ◽  
Qunrui Ye ◽  
Mathilde Poussin ◽  
Gretchen M. Harms ◽  
Mariangela Figini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Car T Cells ◽  
Human T Cell ◽  
Human T Cells ◽  
Car T ◽  
Cd27 Costimulation

AbstractThe costimulatory effects of CD27 on T lymphocyte effector function and memory formation has been confined to evaluations in mouse models, in vitro human cell culture systems, and clinical observations. Here, we tested whether CD27 costimulation actively enhances human T-cell function, expansion, and survival in vitro and in vivo. Human T cells transduced to express an antigen-specific chimeric antigen receptor (CAR-T) containing an intracellular CD3 zeta (CD3ζ) chain signaling module with the CD27 costimulatory motif in tandem exerted increased antigen-stimulated effector functions in vitro, including cytokine secretion and cytotoxicity, compared with CAR-T with CD3ζ alone. After antigen stimulation in vitro, CD27-bearing CAR-T cells also proliferated, up-regulated Bcl-XL protein expression, resisted apoptosis, and underwent increased numerical expansion. The greatest impact of CD27 was noted in vivo, where transferred CAR-T cells with CD27 demonstrated heightened persistence after infusion, facilitating improved regression of human cancer in a xenogeneic allograft model. This tumor regression was similar to that achieved with CD28- or 4-1BB–costimulated CARs, and heightened persistence was similar to 4-1BB but greater than CD28. Thus, CD27 costimulation enhances expansion, effector function, and survival of human CAR-T cells in vitro and augments human T-cell persistence and antitumor activity in vivo.

scholarly journals Immunohistology and immunocytology of human T-cell chimerism and graft- versus-host disease in SCID mice

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3440-3448 ◽  
Author(s):  
G Hoffmann-Fezer ◽  
C Gall ◽  
U Zengerle ◽  
B Kranz ◽  
S Thierfelder
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Graft Versus Host Disease ◽  
Scid Mice ◽  
White Pulp ◽  
Activation Markers ◽  
Host Disease ◽  
Graft Versus Host ◽  
Human T Cell

Surprisingly little graft-versus-host disease (GVHD) has been observed in severe combined immunodeficient (SCID) mice injected intraperitoneally (IP) with human blood lymphocytes (hu-PBL-SCID), which raised the question as to whether GVHD in such a distant species is sporadic or suppressed because of immunologic reasons. After screening for blood T-cell chimerism, we hereby describe generalized lethal xenogeneic human GVHD in unconditioned SCID chimeras, which resembles GVHD in SCID mice injected with allogeneic lymphocytes. We adapted an immunocytochemical slide method for minute cell numbers, which allowed us to follow, by multimarker phenotyping of weekly mouse- tail bleeds, the chimeric status of 100 hu-PBL-SCID injected with 10(7) or 10(8) hu-PBL of Epstein-Barr virus- (EBV-) donors. More than half of the mice showed no or less than 2% T cells. However, 13% to 21% developed substantial blood T-lymphocyte chimerism (10% to 80% human CD+ cells) and high mortality. Immunohistology showed more human CD8+ than CD4+ T cells in the splenic white pulp. The cells developed HLA-DR activation markers and infiltrated the red pulp where human B cells also appeared. Expression of activation and proliferation markers increased within 5 to 6 weeks. Many human CD3+ cells were also found in the portal triads of the liver and in the lung, pancreas, and kidney. The thymus also became heavily infiltrated. The intestines and skin of hu-PBL-SCID were less infiltrated by donor cells than in SCID with allogeneic GVHD. The tongue contained almost no human T cells. Our data show that a relatively low overall incidence of human xenogeneic GVHD, even when high numbers of human PBL are injected, is the consequence of a dichotomy between mice with no or transient T-cell chimerism and a minority of mice with high-blood T-lymphocyte chimerism and GVHD mortality.

Functional Analyses of Human T Cell Extravasation in a Humanized NOD/SCID/IL2Rγcnull Transplantation Model.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2448-2448
Author(s):  
Ariane Brunk ◽  
Marion Nonn ◽  
Victoria Lang ◽  
Reinhard Henschler ◽  
Wolfgang Herr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Skin Substitutes ◽  
Nsg Mice ◽  
Human T Cell ◽  
Human T Cells ◽  
Graft Engineering ◽  
Transplantation Model

Abstract Abstract 2448 Poster Board II-425 Donor lymphocyte graft engineering to avoid graft-versus-host (GVH) reactivity while improving graft-versus-leukemia (GVL) immunity remains of central interest in allogeneic hematopoietic stem cell transplantation (HSCT). However, appropriate models to evaluate experimental concepts of donor lymphocyte allograft engineering in vivo are missing. We, therefore, established a human-murine chimeric transplantation model using immunodeficient NOD/SCID/IL2Rγcnull (NSG) mice to evaluate GVH reactivity of human T cell grafts in vivo. Moreover, since mechanisms of immune functions resembling human GVH immunity have not yet been addressed in detail in these humanized mice we started to analyse T cell trafficking and homing to lymphoid tissues across species barrier to examine the clinical relevance of T cell activity observed in this model. To this end, skin substitutes composed of human primary allogeneic fibroblasts embedded in a collagen-based matrix were subcutaneously implanted into NSG mice to detect alloreactive specificities within the implant post adoptive transfer of MHC-mismatched or haploidentical donor T lymphocytes. The skin substitutes revealed murine vascularisation two weeks after implantation as demonstrated by immunohistological studies. Following transfer of human HLA-mismatched or haploidentical T lymphocytes, up to 23% of the T cells migrated into skin substitutes explanted 21 days post injection. As this T cell migration and homing involves both murine and human adhesion molecules we further analyzed the specific adhesion mechanisms underlying the egress of human T cells from the murine bloodstream. Using laminar flow chamber experiments and real time video recordings we could first demonstrate that human anti-CD3/anti-CD28 preactivated T lymphocytes but not naive T cells bound and firmly adhered to the murine endothelial cell line bEND.3 (BEND3.EC) at shear stresses of up to 3.5 dynes/cm2. As controls, human umbilical vein endothelial cells (HUVEC) were used. Adhesion and transmigration was significally enhanced when both human and murine endothelial cells (ECs) were prestimulated with low doses of TNF-α (5-20ng/ml) to resemble an activated phenotype. Firm adhesion of activated T lymphocytes was suppressed following pretreatment with function-blocking anti-integrin-alpha 4 (CD49d, subunit of VLA-4) or anti-integrin-alpha L (CD11a, subunit of LFA-1) antibody (Ab) or when ECs were preincubated with anti-VCAM-1 (CD106). No inhibitory effects were observed when anti-Endoglin (CD105) Ab was included as specificity control suggesting that the integrin dimer VLA-4 and its counter-receptor VCAM-1 as well as the integrin dimer LFA-1 are required for the transmigration of human T cells across murine ECs. Primary ECs derived from murine aorta are currently used to confirm our results obtained with bEND.3 cells. As the same ligand-receptor pairs are described for human T-EC interaction these findings indicate a closely related mechanism of T cell extravasation in human and murine endothelium at least in our transplantation model. In conclusion these results suggest that intravenously transferred activated human T cells migrate into allogeneic skin substitutes involving VCAM-1 and integrin-alpha-4 for firm adhesion followed by transmigration. In vivo studies investigating the effects of the function-blocking antibodies against VCAM-1 and integrin-alpha-4 in our model to confirm the in vitro results are in progress and will be reported. In addition, our human-murine chimeric NSG transplantation model may represent a promising tool to study human GVH biology and to evaluate T cell graft engineering in allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Limits of the Human-PBL-SCID Mice Model: Severe Restriction of the Vβ T-Cell Repertoire of Engrafted Human T Cells

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 329-336 ◽  
Author(s):  
Sylvie Garcia ◽  
Gilles Dadaglio ◽  
Marie-Lise Gougeon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Scid Mice ◽  
Phenotypic Characterization ◽  
T Cell Repertoire ◽  
Severe Restriction ◽  
Cell Repertoire ◽  
Activation Markers ◽  
Human T Cells

Abstract A recent study in the human-peripheral blood lymphocytes-severe combined immunodeficiency (hu-PBL-SCID) model, analyzing the specificity of the engrafted human T cells, showed that human T-cell lines and clones derived from engrafted cells presented a xenoreactivity toward murine host molecules. This observation raised the question of the influence of the SCID environment on the ex vivo repertoire and function on the human T cells reconstituting the murine host. We have characterized the human Vβ repertoire in the spleen of hu-PBL-SCID mice 1 to 3 months after their engraftment. Fluorescence-activated cell sorting (FACS) analysis of human Vβ T-cell representation showed that, for all chimeras, all tested Vβ subsets were submitted to underrepresentation and/or expansion upon engraftment. Importantly, these quantitative modifications of the T-cell repertoire were associated with a severe restriction in both the CDR3 size distribution pattern of the Vβ transcripts and the number of Jβ segments used by these transcripts. In addition, ex vivo phenotypic characterization of engrafted cells showed that 70% to 100% expressed the activation markers HLA-DR, CD45RO, and CD38. Taken together, these results suggest that, following their engraftment, human T cells were submitted to a massive antigenic selection. Moreover, we found that these activated T cells were unresponsive to in vitro mitogenic and superantigenic activation. The consequences of the skewed repertoire and altered function of engrafted human T cells on the validity of this humanized murine model are discussed.

scholarly journals Cure of disseminated xenografted human Hodgkin's tumors by bispecific monoclonal antibodies and human T cells: the role of human T-cell subsets in a preclinical model

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2930-2937 ◽  
Author(s):  
C Renner ◽  
S Bauer ◽  
U Sahin ◽  
W Jung ◽  
R van Lier ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Scid Mice ◽  
T Cell Subsets ◽  
Human T Cell ◽  
Human T Cells

Cure of a single established human Hodgkin's tumor growing subcutaneously in severe combined immunodeficient (SCID) mice can be achieved with a complex protocol using two bispecific monoclonal antibodies (Bi-MoAb) directed against the Hodgkin's associated CD30 antigen and the T-cell triggering molecules CD3 and CD28, respectively, together with human T cells prestimulated in vitro with Bi-MoAbs in the presence of CD30+ cells. To adapt this model to the clinical situation, disseminated tumors were established in SCID mice by intravenous injection of 2 x 10(7) cells of the Hodgkin's derived cell line L540CY. Treatment of SCID mice bearing disseminated CD30+ Hodgkin's tumors with the combination of CD3/CD30 and CD28/CD30 Bi-MoAbs and naive (ie, not in vitro prestimulated) human T cells resulted in the cure of all appropriately treated animals. T lymphocytes obtained from patients with advanced stage untreated Hodgkin's disease were as effective as lymphocytes from healthy controls. Treatment was effective even when delayed until 2 weeks after tumor inoculation, and application of Bi- MoAbs into SCID mice with circulating human T cells was as effective as injecting the Bi-MoAbs before the lymphocytes. Treatment results with isolated CD4+ and CD8+ human T cells suggest that both subsets are necessary for the Bi-MoAb mediated cure of xenografted human tumors in vivo. The efficacy and practicability of this preclinical immunotherapy protocol support and form the basis for the clinical evaluation of this approach in patients with Hodgkin's disease resistant to standard therapy.

scholarly journals IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2610-2619 ◽  
Author(s):  
Raffaello Cimbro ◽  
Lia Vassena ◽  
James Arthos ◽  
Claudia Cicala ◽  
John H. Kehrl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Critical Role ◽  
Activation Markers ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Human T Cells ◽  
Immunologic Reconstitution

Abstract Interleukin-7 (IL-7) is a nonredundant cytokine that plays a critical role in T-cell homeostasis and promotes immunologic reconstitution in lymphopenic hosts. Here, we show that IL-7, at doses that reflect suprahomeostatic concentrations achieved in lymphopenic hosts, is a potent and selective inducer of the gut-homing integrin α4β7 in human T cells, as documented both ex vivo and in vivo in patients enrolled in a clinical trial of IL-7 treatment. Induction of α4β7 by IL-7 occurs primarily in naive T cells and is associated with functional activation of the integrin, as indicated by increased binding activity for the specific α4β7 ligand, MAdCAM-1. The physiologic relevance of these findings was validated by the preferential homing of IL-7–treated naive human T cells to the intestinal compartment in humanized NOD/SCID/IL-2 receptor-γnull (NSG) mice. We also show that IL-7 triggers a peculiar activation program in naive T cells, characterized by the acquisition of memory-like phenotypic features and proliferation uncoupled from expression of classic T-cell activation markers. These findings provide a mechanism for the transient in vivo depletion of circulating T cells after IL-7 administration and suggest that intestinal homing and memory-like conversion of naive T cells are critical steps in the IL-7–driven immunologic reconstitution of lymphopenic hosts.

Blockade of Cd40-Cd154 Interferes with Human T cell Engraftment in Scid Mice

1998 ◽  
Vol 7 (1) ◽  
pp. 25-35 ◽  
Author(s):  
Teresa M. Foy ◽  
Melissa Mcilraith ◽  
Sally R. Masters ◽  
Jonathan J. Dunn ◽  
Aldo A. Rossini ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Scid Mice ◽  
Antibody Responses ◽  
Cell Engraftment ◽  
Human T Cell ◽  
Human T Cells ◽  
Antigen Presenting ◽  
Possible Cause

Antibodies to the ligand for CD40 (CD154) have been shown to exert profound effects on the development of cell-mediated immune responses in mice. The present study shows that an antibody to human CD154 (hCD40L) inhibits in vivo Tetanus toxoid (TT) specific secondary antibody responses in hu-PBL-scid mice, as well as the expansion of xenoreactive human T cells in the scid mice. A possible cause for the reduced expansion of xenoreactive, human T cells, was the decreased expression of murine B7.1 and B7.2 caused by the administration of anti-hCD40L. Therefore, it may be that defective maturation of murine antigen-presenting cells impeded the priming and expansion of human xenoreactive T cells.

scholarly journals Human mature T cells that are anergic in vivo prevail in SCID mice reconstituted with human peripheral blood.

1992 ◽  
Vol 175 (2) ◽  
pp. 503-516 ◽  
Author(s):  
M Tary-Lehmann ◽  
A Saxon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Critical Role ◽  
Scid Mice ◽  
Human T Cell ◽  
Human T Cells ◽  
T Cell Lines

In these studies we have characterized the human cells that repopulate severe combined immunodeficient (SCID) mice after injection of adult peripheral blood or cord blood (hu-PBL-SCID mice). In all organs of the chimeras, and at any time point tested, single-positive (CD4+ or CD8+) T cells that expressed the alpha/beta T cell receptor (TCR) prevailed. All T cells were CD45RO+ and the majority were also HLA-DR+. Thus, the human T cells in the chimeras exhibited the phenotype of mature, memory cells that showed signs of recent activation. Cell cycle studies revealed a mitotically active human T cell population in the murine host. However, when freshly isolated from the chimeras, the human T cells were refractory to stimulation by anti-CD3 antibody but proliferated in response to exogenous interleukin 2. Chimera-derived human T cell lines retained this state of unresponsiveness to TCR-triggered proliferation for 4-6 wk in vitro. Subsequently, the T cell lines developed responses to anti-CD3 stimulation and 9 of 11 of the lines also proliferated in response to splenic stimulator cells of SCID mice. These data demonstrate that the human T cells are in a state of reversible anergy in the murine host and that xenoreactivity might play a critical role in hu-PBL-SCID mice. Mechanisms that may determine repopulation of SCID mice with human peripheral blood mononuclear cells are discussed.

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