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Differentiation of Th1 Cells Expansion but Fails to Prevent the Peripheral Peripheral Immune Tolerance Blocks Clonal Expansion but Fails to Prevent the Differentiation of Th1 Cells This information is current as Erika-Nell Malvey, Marc K. Jenkins and Daniel L. Mueller of September 23, 2021. J Immunol 1998; 161:2168-2177; ; http://www.jimmunol.org/content/161/5/2168 Downloaded from References This article cites 55 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/161/5/2168.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Peripheral Immune Tolerance Blocks Clonal Expansion but Fails to Prevent the Differentiation of Th1 Cells1 Erika-Nell Malvey,* Marc K. Jenkins,† and Daniel L. Mueller2* Clonal anergy in Ag-specific CD41 T cells is shown in these experiments to inhibit IL-2 production and clonal expansion in vivo. We also demonstrate that the defect in IL-2 gene inducibility can be achieved in both naive and Th1-like memory T cells when repeatedly exposed to aqueous peptide Ag. Nevertheless, this induction of clonal anergy did not interfere with the capacity of naive T cells to differentiate into Th1-like effector cells, nor did it prevent such helper cells from participating in T-dependent IgG2a anti-hapten responses and delayed-type hypersensitivity reactions. Thus, clonal anergy can contribute to the development of Ag-specific immune tolerance by limiting the size of a Th cell population, but not by disrupting its effector function. The Journal of Immunology, 1998, 161: 2168–2177. Downloaded from he immune system has the remarkable ability to mount a naling cascades (17–19) necessary for the induction of activating highly specific response against invading pathogens while protein-1-dependent IL-2 gene transcription (20–22). Importantly, T ignoring self molecules. This specificity is determined in the clonal anergy observed in vitro has not been associated with a part by the T lymphocyte, which expresses a randomly generated global defect in T cell activation events. Specifically, the secretion and unique TCR that recognizes a peptide Ag bound to an MHC of IFN-g by anergic CD41 Th cells is not blocked after the in- molecule (1). Because MHC molecules can bind both self as well 1 duction of clonal anergy (23). Furthermore, anergic CD8 CTL are http://www.jimmunol.org/ as foreign peptides, the specificities of the peripheral TCR reper- capable of lysing target cells (24). Finally, anergy induction cannot toire or function of self-reactive T cells must be regulated such that effectively interfere with the delivery of helper signals for the stim- the immune system ignores the self peptides. The physical elimi- ulation of B cell polyclonal IgG secretion in vitro (25). Consistent nation of autoreactive T cells during thymocyte development is the with these functional results, anergic T cells can be shown to de- primary mechanism used by the immune system to establish such velop increases in intracellular calcium free ion concentrations that self-tolerance (2, 3). However, not all self peptides are present in result in the dephosphorylation and nuclear translocation of the the thymus. Therefore, the immune system must either ignore a nuclear factor of activated T cells (NFAT) upon stimulation (22). tissue-specific self peptide (4), or develop an active self-tolerance Thus, the clonal anergy mechanism appears to selectively interrupt that relies on the suppression (5, 6), physical elimination (7, 8), or signal transduction to the nucleus, resulting in a defective prolif- by guest on September 23, 2021 functional inactivation (9, 10) of mature autoreactive T cells. erative capacity, yet it may not eliminate the potential of a T cell Inactivation of T cells by the tolerance mechanism called clonal to participate in an effector cell response. anergy was originally described using a tissue culture system of These findings of selectivity in the inhibitory effects of clonal cloned T cells (11, 12). Clonal anergy has since been defined as a anergy raise uncertainty as to how this mechanism might contrib- reversible, induced tolerance state in which the T lymphocyte can- ute to the development of immune tolerance in vivo. Proliferative not produce its autocrine growth factor IL-2 or proliferate in re- T cell clonal anergy has previously been reported in animals made sponse to the Ag it recognizes (13). In vitro, this unresponsive state tolerant of foreign Ag by the systemic administration of aqueous is induced by stimulation of the T cell through its TCR in the peptides in the absence of infection or adjuvant (26). Clonal anergy absence of costimulatory signals, such as those occurring as a re- has also been observed after the systemic exposure of animals to sult of the interaction of B7 molecules on the APC with CD28 superantigens such as staphylococcal enterotoxin B (SEB)3 (27). receptors on the T cell (14, 15). In the absence of such costimu- Interestingly, TCR-Vb8 transgenic mice immunized against teta- latory signals, T cells fail to proliferate, and TCR occupancy un- nus toxoid showed no evidence of tolerance within the tetanus accompanied by proliferation down-regulates the T cell’s respon- toxoid-specific Th cell population following exposure to SEB, de- siveness (16). Biochemical analyses have suggested that anergic T spite the ability of the SEB to induce proliferative unresponsive- cells lose the capacity to synthesize IL-2 because of a defect in the ness in the naive T cell population (28). Likewise, systemic expo- Ras coupling of the Ag receptor to downstream p21 -dependent sig- sure of naive mice to the lymphocytic choriomeningitis virus (LCMV) glycoprotein-derived peptide GP33 induced tolerance within CD81CTL precursors, whereas mice that had first been † Departments of *Medicine and Microbiology, and Center for Immunology, Univer- infected with LCMV instead developed destructive spleen immu- sity of Minnesota Medical School, Minneapolis, MN 55455 nopathology in response to systemic administration of the aqueous Received for publication February 5, 1998. Accepted for publication April 30, 1998. GP33 peptide (29). These findings suggest either that memory T The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance cells are insensitive to clonal anergy induction, or that the anergy with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This study was supported by a grant from the National Institutes of Health (PO1 AI35296) as well as by a Graduate School Grant-In-Aid research award from the University of Minnesota. E.M. is also supported by an Immunology Pre-Doctoral 3 Abbreviations used in this paper: SEB, staphylococcal enterotoxin B; DTH, de- Training Grant from the National Institutes of Health (AI07313). layed-type hypersensitivity; i.d., intradermal; LCMV, lymphocytic choriomeningitis 2 Address correspondence and reprint requests to Dr. Daniel L. Mueller, University of virus; OVAp, ovalbumin peptide 323–339; Tg, transgenic; IFA, incomplete Freund’s Minnesota Medical School, Box 334 FUMC, Minneapolis, MN 55455. adjuvant. Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 2169 mechanism cannot regulate all effector functions by an expanded T rificed, lymph node and spleen cells were isolated, and the KJ1-261CD41 cell clone in the peripheral immune system. cells were enumerated by flow cytometry. In some experiments, day 30 m Previously, in vivo models of T cell activation have not had the nu/nu mice were then primed s.c. with 100 g OVAp in CFA at the base of the tail and sacrificed at day 40. Alternatively, nu/nu mice were primed power to quantitate the effector cell capabilities of lymphocytes first with OVAp in CFA at day 15, and then tolerized at days 25, 30, and following the induction of an Ag-specific tolerance. Specifically, 35 with i.p. OVAp injections before sacrifice at day 40. T cells isolated differences in the frequencies of Ag-reactive T cells that develop as from these mice were subsequently transferred i.v. into unirradiated syn- a consequence of clonal expansion and/or activation-induced cell geneic BALB/c recipients, such that each host animal received 0.25 to 2 3 106 KJ1-261CD41 donor cells in 0.5 ml PBS. Some of the donor cells death have complicated the analysis. Therefore, we have devel- were also used immediately for in vitro proliferation and lymphokine pro- oped an experimental system that both allows for the induction of duction assays. T cell tolerance in mice using an aqueous peptide Ag, and that permits the subsequent recovery and identification of Ag-specific Flow cytometry cells from these tolerant animals. Using this system, the functional Peripheral blood leukocytes, lymph node cells, or splenocytes were harvested, capacities of equal numbers of normal and tolerant T cells can be and 106 cells were incubated on ice with biotinylated anti-clonotypic mAb directly compared following their adoptive transfer into normal KJ1-26 (31), followed by streptavidin Cy-Chrome (PharMingen, San Diego, CA) together with anti-CD4-phycoerythrin (Caltag, Burlingame, CA).
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