Cell-deficient Recipients Research Articles

Induction of protective immunity by primed B-1 cells in Toxoplasma gondii -infected B cell-deficient mice.

We examined the role of B-1 cells in protection against Toxoplasma gondii infection using B cell-deficient mice (muMT mice). We found that primed but not naïve B-1 cells from wild-type C57BL/6 mice protected B cell-deficient recipients from challenge infection. All muMT mice transferred with primed B-1 cells survived more than 5 months after T. gondii infection, whereas 100% of muMT mice transferred with naïve B-1 cells succumbed by 18 days after infection. Additionally, high expression of both T help (Th) 1- and Th2-type cytokines and a high level of nitric oxide production were observed in T. gondii-infected muMT mice transferred with primed B-1 cells. Thus, it was clearly demonstrated that B-1 cells play an important role in host protection against T. gondii infection in muMT mice.

Stat5 expression is critical for mast cell development and survival

AbstractInterleukin-3 (IL-3) and stem cell factor (SCF) are important mast cell growth and differentiation factors. Since both cytokines activate the transcription factor signal transducer and activator of transcription 5 (Stat5), a known regulator of proliferation and survival, we investigated the effects of Stat5 deficiency on mast cell development and survival. Bone marrow–derived mast cell (BMMC) populations cultured from Stat5A/B-deficient mice survived in IL-3 + SCF, but not in either cytokine alone. These cells demonstrated reduced expression of Bcl-2, Bcl-x(L), cyclin A2, and cyclin B1, with increased apoptosis and delayed cell cycle progression during IL-3 or SCF culture. Finally, the absence of Stat5 resulted in loss of in vivo mast cell development, as judged by assessments of Stat5-deficient mice and transplantation of Stat5-deficient bone marrow cells to mast cell-deficient recipient mice. These results indicate that Stat5A and Stat5B are critical regulators of in vitro and in vivo mast cell development and survival.

Immunopathogenesis of accelerated allograft rejection in sensitized recipients: humoral and nonhumoral mechanisms.

Accelerated rejection (AccR) in sensitized recipients (second-set rejection) is considered a classic humorally mediated form of allograft rejection, although additional effector mechanisms may be involved. We developed a model of AccR in which C57BL6 mice are sensitized by BALB/c skin grafts, followed 10 days later by transplantation of BALB/c hearts. We undertook analysis of various humoral and cellular components in this model using knockout or monoclonal antibody-treated allograft recipients. Sensitized mice rejected cardiac allografts in 34+/-7 hr. AccR was accompanied by endothelial deposition of immunoglobulins, complement, and fibrin, but also by dense expression of multiple chemokines and a mixed polymorphonuclear and mononuclear cellular infiltrate. Whereas neutrophil or complement depletion had no significant effect on the tempo of AccR, surprisingly B cell-deficient recipients still underwent AccR (41+/-7 hr) in conjunction with T cell and macrophage recruitment. In contrast, T cell-deficient (nude) mice maintained functioning cardiac allografts for >720 hr despite prior skin engraftment. AccR in sensitized experimental recipients involves multiple effector pathways. Although most previous studies have emphasized the key role of humoral pathways in mediating AccR, our data indicate that T cell-dependent mechanisms can also promote AccR, alone or in conjunction with humoral responses.

Contributions from self-renewal and trafficking to the uterine NK cell population of early pregnancy.

Uterine NK (uNK) cells are abundant in human and murine uteri during decidualization. It is unclear whether precursors of uNK (pre-uNK) cells self-renew or are recruited from other sites. To assess self-renewal of pre-uNK cells, uterine segments from NK cell-competent mice were grafted orthotopically into NK/uNK cell-deficient or wild-type mice. Only in wild-type recipients did decidualized grafts contain uNK cells, indicating that pre-uNK cells do not self-renew in uterus. To identify pre-uNK cell sources, thymus, bone marrow, lymph node, or spleen cells were grafted from virgin or pregnant NK cell-competent donors into mated NK/uNK cell-deficient recipients. Cells from secondary lymphoid tissues of pregnant donors gave high level uNK cell reconstitution, which was independent of chemokine receptors CCR2 or CCR5. Pregnancy-induced changes to lymphocyte-endothelial cell interactions were documented using adhesion of human lymphocytes to frozen mouse tissue sections under shear. A dynamic increase was observed in L-selectin- and alpha(4) integrin-dependent adhesion of CD56(bright) NK cells to decidualizing uterus and in human PBL adhesion to lymph node endothelium. These data support a model that attributes the dramatic increases in human and murine uNK cells during decidualization to precursor cell recruitment.

Extracellular nicotinamide adenine dinucleotide induces t cell apoptosis in vivo and in vitro.

Incubation of mouse T cells expressing the cell surface enzyme ADP ribosyltransferase with nicotinamide adenine dinucleotide (NAD) had been reported to cause ADP ribosylation of cell surface molecules, inhibition of transmembrane signaling, and suppression of immune responses. In this study, we analyze the reasons for these effects and report that contact of T cells with NAD causes cell death. Naive T cells when incubated with NAD and adoptively transferred into semiallogeneic mice fail to cause graft-vs-host disease, and when injected into syngeneic, T cell-deficient recipients do not reconstitute these mice. Rather, they accumulate in the liver, leading to an increase of apoptotic lymphocytes in this organ. Similar effects are induced by injection of NAD, shown to cause a dramatic increase of apoptotic CD3(+), CD4(+), and CD8(+) cells in the liver. Consistent with this, in vitro incubation of naive T cells with NAD is shown to induce apoptosis. In contrast, no cell death is demonstrable when T cells are activated before incubation with NAD. It is concluded that ecto-NAD, as substrate of ADP ribosyltransferase, acts on naive, but not on activated CD69(+) T cells.

The role of alpha beta+ T cells and homeostatic T cell proliferation in Y-chromosome-associated murine lupus.

Male BXSB mice develop an early life, severe lupus-like disease largely attributed to an undefined Y-chromosome-associated autoimmunity accelerator, termed YAA: Although the exact disease pathogenesis is uncertain, indirect evidence suggests that T cells play an important role in the male BXSB disease. We have developed TCR alpha-chain gene-deleted BXSB mice to directly examine the role of alphabeta+ T cells and the mode by which Yaa promotes disease in this strain. All disease parameters, including hypergammaglobulinemia, autoantibody production, glomerulonephritis, and the unique monocytosis of BXSB males, were severely reduced or absent in the alphabeta+ T cell-deficient mice. Adoptively transferred CD4+ T cells of either male or female BXSB origin showed equal homeostatic proliferation in alphabeta+ T cell-deficient male recipients. Moreover, deficient male mice eventually developed equally severe lupus-like disease after adoptive transfer and homeostatic expansion of T cells from wild-type BXSB males or females. The results directly demonstrate that the Yaa-mediated disease requires alphabeta+ T cells that are not, in themselves, abnormal in either composition or properties, but are engaged by a Yaa-encoded abnormality in a non-T cell component. In addition, homeostatic anti-self proliferation of mature T cells derived from a small number of precursors can induce systemic autoimmunity in an appropriate background.

Cd4+ T Cell Subsets during Virus Infection

To analyze the antiviral protective capacities of CD4(+) T helper (Th) cell subsets, we used transgenic T cells expressing an I-A(b)-restricted T cell receptor specific for an epitope of vesicular stomatitis virus glycoprotein (VSV-G). After polarization into Th1 or Th2 effectors and adoptive transfer into T cell-deficient recipients, protective capacities were assessed after infection with different types of viruses expressing the VSV-G. Both Th1 and Th2 CD4(+) T cells could transfer protection against systemic VSV infection, by stimulating the production of neutralizing immunoglobulin G antibodies. However, only Th1 CD4(+) T cells were able to mediate protection against infection with recombinant vaccinia virus expressing the VSV-G (Vacc-IND-G). Similarly, only Th1 CD4(+) T cells were able to rapidly eradicate Vacc-IND-G from peripheral organs, to mediate delayed-type hypersensitivity responses against VSV-G and to protect against lethal intranasal infection with VSV. Protective capacity correlated with the ability of Th1 CD4(+) T cells to rapidly migrate to peripheral inflammatory sites in vivo and to respond to inflammatory chemokines that were induced after virus infection of peripheral tissues. Therefore, the antiviral protective capacity of a given CD4(+) T cell is governed by the effector cytokines it produces and by its migratory capability.

Transplantation into Genetically Alymphoid Mice as an Approach to Dissect the Roles of Uterine Natural Killer Cells during Pregnancy— A Review

Mice genetically deficient in the natural killer (NK) cell lineage lack uterine (uNK cells) and demonstrate morphometrically-quantifiable histopathology within their implantation sites. Two particular mouse strains, tgϵ,26 and RAG-2 null×γc null, have been used successfully as transplant recipients to address questions relating to the biology of uNK cells. uNK cells did not differentiate within decidualized uterine graft segments from normal mice, which were anastomosed orthotopically into immunodeficient hosts. uNK cells did appear in similar grafts placed into immunocompetent hosts, indicating that uNK cells or their progenitors must home to the uterus. This was confirmed by splenocyte transplantation into pregnant uNK cell deficient recipients. Only splenocytes from pregnant donors, not those from non-pregnant donors, homed to the uterus. Homing in this in vivo assay was independent of the CC-chemokine receptors, CCR-2 and CCR-5. Longer-term bone marrow cell reconstitution of neonatal or virgin adult uNK cell-deficient mice has identified a functional role for uNK cells in modification of the decidual arterioles which is mediated by IFN-γ. By utilizing mutant and gene-ablated mice as donors for tissue or haematopoietic cell transplants to uNK cell deficient mice, it should be possible to fully characterize the in vivo regulation and functions of these pregnancy-specific uterine lymphocytes.

CD4(+) T cell-mediated protection against a lethal outcome of systemic infection with vesicular stomatitis virus requires CD40 ligand expression, but not IFN-gamma or IL-4.

To investigate the mechanism(s) whereby T cells protect against a lethal outcome of systemic infection with vesicular stomatitis virus, mice with targeted defects in genes central to T cell function were tested for resistance to i.v. infection with this virus. Our results show that mice lacking the capacity to secrete both IFN-gamma and perforin completely resisted disease. Similar results were obtained using IL-4 knockout mice, indicating that neither cell-mediated nor T(h)2-dependent effector systems were required. In contrast, mice deficient in expression of CD40 ligand were more susceptible than wild-type mice, and residual resistance in these mice was almost completely abrogated by depletion of CD8(+) T cells. In keeping with this, mice lacking both MHC class I and class II expression succumbed to the infection, whereas most class II-deficient mice normally survive. Adoptive transfer experiments using B cell- and T cell-deficient recipients revealed that no protection could be obtained in the absence of B cells, whereas treatment with virus-specific immune (IgG) serum controlled viral spreading to the central nervous system (CNS), but did not necessarily accomplish virus elimination. Taken together, these results underscore that B cells are essential in preventing early infection of the CNS, but T cells are required for long-term survival. CD4(+) T cells are most efficient in this context and the key function is to provide cognate help to B cells. However, if CD4(+) cell function is compromised, CD8(+) T cells become critical and may suffice for survival.

Persisting alloantigen prevents primed CD45RC CD4 T cells from inducing allograft rejection: implications for immunological memory

Antigen stimulation induces specific CD4 T cells to change from a resting phenotype (CD45RC + ) to a “memory” phenotype (CD45RC − ), an isoform switch that is reversible and regulated by persisting antigen. We show here that CD4 T cells responsible for mediating allograft rejection undergo a similar CD45RC + to CD45RC − switch irrespective of whether antigen priming results in sensitization or tolerance in vivo. Thus, skin allograft priming, designed to induce second set rejection, and a donor-specific blood transfusion (DST), designed to prolong cardiac allograft survival, will generate CD45RC − CD4 T cells that induce acute rejection when adoptively transferred to T cell-deficient athymic nude recipients. The ability of CD45RC − T cells, obtained from DST donors, to induce graft rejection was prevented by giving nude recipients a DST 14, 28 or even 56 days before grafting and T cell transfer. Thus, prolonged allograft survival in rats after DST was found to be strongly linked with persisting alloantigen from the blood transfusion but was not associated with detectable microchimerism. Importantly, CD45RC − T cells from skin graft-primed animals were similarly prevented from inducing rejection by residual DST-derived alloantigen. The investigation shows (1) that an allogeneic blood transfusion primes (not tolerizes) alloreactive CD4 T cells and (2) that residual DST-derived alloantigen can block the action of specifically primed “memory” CD4 T cells. These findings have implications for understanding immunological memory.

Persisting alloantigen prevents primed CD45RC- CD4 T cells from inducing allograft rejection: implications for immunological memory.

Antigen stimulation induces specific CD4 T cells to change from a resting phenotype (CD45RC+) to a "memory" phenotype (CD45RC-), an isoform switch that is reversible and regulated by persisting antigen. We show here that CD4 T cells responsible for mediating allograft rejection undergo a similar CD45RC+ to CD45RC- switch irrespective of whether antigen priming results in sensitization or tolerance in vivo. Thus, skin allograft priming, designed to induce second set rejection, and a donor-specific blood transfusion (DST), designed to prolong cardiac allograft survival, will generate CD45RC- CD4 T cells that induce acute rejection when adoptively transferred to T cell-deficient athymic nude recipients. The ability of CD45RC- T cells, obtained from DST donors, to induce graft rejection was prevented by giving nude recipients a DST 14, 28 or even 56 days before grafting and T cell transfer. Thus, prolonged allograft survival in rats after DST was found to be strongly linked with persisting alloantigen from the blood transfusion but was not associated with detectable microchimerism. Importantly, CD45RC- T cells from skin graft-primed animals were similarly prevented from inducing rejection by residual DST-derived alloantigen. The investigation shows (1) that an allogeneic blood transfusion primes (not tolerizes) alloreactive CD4 T cells and (2) that residual DST-derived alloantigen can block the action of specifically primed "memory" CD4 T cells. These findings have implications for understanding immunological memory.

Qualitative and Quantitative Requirements for CD4+ T Cell-Mediated Antiviral Protection

CD4+ Th cells deliver the cognate and cytokine signals that promote the production of protective virus-neutralizing IgG by specific B cells and are also able to mediate direct antiviral effector functions. To quantitatively and qualitatively analyze the antiviral functions of CD4+ Th cells, we generated transgenic mice (tg7) expressing an MHC class II (I-Ab)-restricted TCR specific for a peptide derived from the glycoprotein (G) of vesicular stomatitis virus (VSV). The elevated precursor frequency of naive VSV-specific Th cells in tg7 mice led to a markedly accelerated and enhanced class switching to virus-neutralizing IgG after immunization with inactivated VSV. Furthermore, in contrast to nontransgenic controls, tg7 mice rapidly cleared a recombinant vaccinia virus expressing the VSV-G (Vacc-IND-G) from peripheral organs. By adoptive transfer of naive tg7 CD4+ T cells into T cell-deficient recipients, we found that 105 transferred CD4+ T cells were sufficient to induce isotype switching after challenge with a suboptimal dose of inactivated VSV. In contrast, naive transgenic CD4+ T cells were unable to adoptively confer protection against peripheral infection with Vacc-IND-G. However, tg7 CD4+ T cells that had been primed in vitro with VSV-G peptide were able to adoptively transfer protection against Vacc-IND-G. These results demonstrate that the antiviral properties of CD4+ T cells are governed by the differentiation status of the CD4+ T cell and by the type of effector response required for virus elimination.

ALLOANTIBODY- AND T CELL-MEDIATED IMMUNITY IN THE PATHOGENESIS OF TRANSPLANT ARTERIOSCLEROSIS

The relative roles of humoral and cell-mediated immunity in generating chronic allograft arteriopathy have been considered for several years. We have sought definitive evidence regarding these questions using heart transplants between mouse strains selected to isolate the effects of each form of immune responsiveness. B10.BR hearts were transplanted to B cell-deficient recipients that are devoid of immunoglobulins (muMT). Their vessels were compared with those of transplants to fully reactive recipients of the same genetic background (C57BL/6). Additional evidence came from comparisons in other strain combinations. Transplants to B cell-deficient and normal recipients developed cellular coronary endothelialitis, with destruction of the arterial media, accompanied by the adherence of T lymphocytes and macrophages to endothelial surfaces. In B cell-deficient recipients, there was no centripetal migration of smooth muscle, alpha-actin-positive myointimal cells and little deposition of collagen or ground substance, compared with lesions in fully reactive C57BL/6 recipients in which these changes are prominent. In two other donor-recipient combinations in which anti-donor antibodies are generally undetectable (B10.BR-->B10.A and 129-->C57BL/6), intimal fibrosis was uncommon. However, B10.A recipients became capable of producing fibrous lesions in B10.BR hearts when given anti-donor, class I antibody by passive transfer, as we have observed previously in scid recipients. Taken together, these findings indicate that endothelialitis is antibody-independent, whereas antibodies potentiate and can be sufficient for fully developed, fibrous, chronic allograft vasculopathy. Therapeutic strategies for controlling chronic lesions must consider inhibition of the humoral response.

Treatment with either anti-CD4 or anti-CD8 monoclonal antibodies blocks alphabeta T cell-mediated rejection of intestinal allografts in mice.

Rejection is the major barrier preventing the more widespread application of intestinal transplantation as treatment for intestinal failure. For this study, a one-way host-versus-graft murine model was used to investigate the contribution of T cell subsets to the rejection of allogeneic intestinal allografts. Intestinal grafts consisting of the donor jejunum and ileum were procured from C57BL/6J (syngeneic group) and B6C3F1/J (C57BL/6 x C3H/HeJ, allogeneic group) mice. These grafts were then transplanted into (1) normal, (2) antibody-treated, or (3) genetically mutated C57BL/6 mice. Mice were killed at predetermined intervals and the grafts assessed for rejection by a blinded pathologist. No syngeneic mice demonstrated any evidence of rejection. In contrast, the recipients of allografts experienced progressive rejection. Recipient mice treated with tacrolimus developed significantly less severe allograft rejection. None of the alphabeta T cell-deficient recipient mice (T cell receptor beta chain knockout mice) experienced allograft rejection with follow-up ranging from 8 to 28 days. However, mice deficient in gammadelta T cells (T cell receptor delta chain knockout mice) rejected intestinal allografts in a manner indistinguishable from normal recipients. In order to investigate the role of CD4+ and CD8+ T cells, recipient mice were treated 2 days before transplantation with depleting monoclonal antibodies specific for either CD4+ cells or CD8+ cells. Depletion of either population of cells significantly inhibited allograft rejection. These data demonstrate that rejection of intestinal allografts in the murine model was absolutely dependent on alphabeta but not gammadelta T cells. Furthermore, both CD4+ and CD8+ T cells were necessary for small bowel allograft rejection. Additional studies will be required to determine whether the effects of monoclonal antibody treatment were due solely to depletion of T cells or were mediated at least in part through an active process that altered the functional properties of the targeted T cell subset.

Cell division in the compartment of naive and memory T lymphocytes.

Expression of activation markers and proliferative status were measured in peripheral CD4+ and CD8+ T cells of various T cell receptor (TCR)-transgenic mice either before or after intentional antigenic stimulation. In the absence of intentional immunization, CD4+ T cells persisted as resting or partially activated and cycling cells depending on the specificity of their TCR. Similar results were obtained following transfer into T cell-deficient recipients, i.e. T cells that were not cycling in situ did not cycle after transfer, whereas cells that were proliferating in situ also cycled after transfer. Thus, the TCR of some cells in the absence of intentional antigenic stimulation may bind to some unidentified ligand that does not induce tolerance, but rather slow expansion. In a different sort of experiment, activated T cells that were derived from noncycling naive T cells by deliberate antigenic stimulation continued to cycle slowly even a long time after transfer into antigen-free recipients that did not induce proliferation of the naive cells. Thus, lymphokines or ligands that do not induce activation of naive T cells may be responsible for the maintenance of memory cells. Our experiments show that the latter does not depend on a second TCR expressed by the memory cells, since memory T cells from RAG-2(-/-) TCR-transgenic mice persisted to a similar extent.

Islet allograft, islet xenograft, and skin allograft survival in CD8+ T lymphocyte-deficient mice.

Despite extensive study, the immunologic mechanisms mediating allograft rejection have not been completely defined. In the current study, we evaluated the T cell subsets important in islet allograft, skin allograft, and islet xenograft rejection using a genetically engineered line of mice deficient in beta 2-microglobulin expression. Because these mice lack cell surface MHC class I expression, they are deficient in T cells of the CD8 subset (class I-restricted cytotoxic T cells). Pancreatic islet allografts transplanted to CD8+ T cell-deficient recipients showed prolonged survival compared with controls. No prolongation was observed in the survival of pancreatic islet xenografts or in the survival of skin allografts transplanted to the CD8+ T cell--deficient hosts. We conclude that CD8+ T cells play a prominent role in islet allograft, but not islet xenograft or skin allograft, rejection in mice.

Antiviral effect of lymphokine-activated killer cells: characterization of effector cells mediating prophylaxis

Lymphokine-activated killer (LAK) cells generated by cultivation of C57BL/6 mouse spleen cells in the presence of recombinant interleukin-2 were transferred into natural killer (NK) cell-deficient suckling mouse recipients. These mice were then challenged with either murine cytomegalovirus (MCMV) or lymphocytic choriomeningitis (LCMV) and sacrificed 3 days later. No interleukin 2 infusions were given. Mice receiving as few as 5 x 10(5) LAK cells had several 100-fold decreases in spleen MCMV titers as compared with untreated mice. This treatment had no effect on spleen LCMV titers. The LAK cell cultures contained 10 to 17% NK 1.1+, 50 to 55% Lyt-2+, and 33 to 50% immunoglobulin D+ cells. Double fluorescence labeling and in vitro cytotoxicity assays with fluorescence-activated cell sorting revealed at least two mutually exclusive killer cell populations. NK 1.1+ LAK cells resembled freshly isolated activated NK cells with regard to target cell range (YAC-1 cell killing greater than L-929, P815, and EL-4 cell killing), large granular lymphocyte (LGL) morphology, and decreased ability to lyse interferon (IFN)-treated target cells. Lyt-2+ LAK cells lysed the targets mentioned above but at lower levels and without the differences in susceptibility mentioned above. These Lyt-2+ LAK cells also had a decreased ability to lyse IFN-treated targets, in contrast to classic cytotoxic T lymphocytes, which lyse IFN-treated targets far more efficiently than untreated targets. Purified populations of LAK cells obtained by fluorescence-activated cell sorting were used in the antiviral protection model. The results showed that protection against MCMV could be mediated by NK 1.1+, NK 1.1-, Lyt-2+, Lyt-2-, and IgD- populations but not by IgD+ cells. The five protective populations all had in common the LGL phenotype and cytotoxic activity in vitro. The IgD+ population did not contain LGLs, lyse target cells in vitro, or mediate an antiviral effect in vivo. These results suggest that LAK cells may be therapeutically useful against certain virus infections (MCMV) but not others (LCMV) and that despite their heterogeneity in antigenic phenotype and cytotoxic activity, their pattern of antiviral activity in vivo resembles that of NK cells, which protect against MCMV but not LCMV.

The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis.

Mice infected i.v. with the virulent Erdman strain of Mycobacterium tuberculosis exhibited three distinct phases of infection within the spleen. These consisted of a primary phase, characterized by the progressive growth of the organism; a secondary phase, in which the viable organism was progressively eliminated; and a tertiary phase, characterized by a chronic or slowly recrudescing disease state. Passive transfer experiments, in which T cell-enriched spleen cells from immune donors were infused into T cell-deficient recipients and were measured for their capacity to adoptively protect these mice from challenge with M. tuberculosis, provided evidence that at least three separate populations of protective T cells were acquired in response to the infection within the time frame of the experiments. These populations of T cells could be distinguished in that they differed in their expression of the L3T4 and Lyt-2 cell surface molecules, in terms of their kinetic profiles of emergence and loss, and (c) in terms of their susceptibility to cyclophosphamide. The results may suggest that different populations of protective T cells can be generated at different times during the infection as various classes of antigens (for example, metabolic or structural antigens) become available for presentation by host macrophages. It is hypothesized, furthermore, that the kinetics of emergence and loss of these various populations may reflect switching in the mode of immunity being expressed, particularly during the chronic phase of the infection, from that of a state of active immunity to one of immunologic memory.

T cell suppressors of antitumor immunity. The production of Ly-1-,2+ suppressors of delayed sensitivity precedes the production of suppressors of protective immunity.

The results of this study show that during growth of the immunogenic Meth A fibrosarcoma, two different types of suppressor T lymphocytes are generated in sequence. One type is generated during early tumor growth, reaches peak number around day 6, and is progressively lost thereafter. It is defined by its ability, upon passive transfer, to suppress the expression of a DTH reaction to tumor antigens in tumor-immunized recipients. It bears the Ly1-,2+ membrane phenotype and is sensitive to relatively low doses of cyclophosphamide. In contrast, the second type of suppressor cell is not detected until after day 9 of tumor growth, and is defined by its ability to inhibit, upon passive transfer, the expression of adoptive immunity against an established tumor in T cell-deficient recipients. According to previous studies it bears the Ly1+,2-, L3T4a+ membrane phenotype and is less sensitive to cyclophosphamide than the T cell suppressor of DTH. It is argued that this second type of suppressor T cell seems likely to be responsible for the escape of immunogenic tumors from antitumor immunity, because it can suppress the expression of a powerful mechanism of antitumor immunity in recipient mice, and is generated progressively as the tumor-bearing host loses concomitant immunity. In contrast, although the Ly-1-,2+ T cell suppressors of DTH can efficiently suppress a DTH reaction to an implant of living tumor cells, they fail to suppress the expression of immunity to the same implant.

Crossprotection against nontuberculous mycobacterial infections by Mycobacterium tuberculosis memory immune T lymphocytes.

Adoptive immunization of T cell-deficient recipient mice with M. tuberculosis-specific memory immune T lymphocytes conferred upon these animals the ability to express significantly enhanced resistance both to the homologous infection, and to three strains of nontuberculous mycobacteria. These results support the hypothesis, therefore, that antigenic determinants possessed by the four mycobacterial strains that are relevant to the generation of protective cellular immunity are identical or closely crossreactive.