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Major Histocompatibility Complex-Restricted MAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED SELF-RECOGNITION IN RESPONSES TO TRINITROPHENYL-FICOLL A Novel Cell Interaction Pathway Requiring Self-Recognition of Accessory Cell H-2 Determinants by Both T Cells and B Cells By RICHARD J. HODES, KAREN S. HATHCOCK, AND ALFRED SINGER From the Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205 Most thymus-dependent (T) lymphocyte populations are restricted in their function by a requirement for recognition of"self" major histocompatibility complex (MHC) 1 gene products. Thus, T cells that mediate help (Tn) (1-5), antigen-specific prolifera- tion (6, 7), cell-mediated lympholysis (8, 9), delayed-type hypersensitivity (10), and immune suppression (11) require recognition of MHC products expressed by the cells with which they interact. In addition to MHC restriction of T cell recognition, the possibility that B cells as well as T cells may be capable of MHC-restricted self- recognition has recently been evaluated (12-15). In a recent report (15), the possibility that trinitrophenyl (TNP)-Ficoll-responsive B cells are MHC restricted in their interaction with accessory cells was assessed under T-independent (TI) response conditions. In the absence of any detectable requirement for T cells, it was demon- strated that TNP-Ficoll-responsive B cells, as a consequence of their development in a fully MHC-allogeneic chimeric host environment, were unable to cooperate with accessory cells expressing syngeneic donor-type MHC determinants but could coop- erate with accessory cells expressing allogeneic host-type MHC products. These findings raised a number of other questions. Although they demonstrated that B cells could express MHC-restricted self-recognition in the absence of T cells, these studies did not determine the effects that T cells or their soluble products could exert on this B cell function. Specifically, it remained undetermined whether restricted recognition by B lymphocytes of accessory cell MHC determinants could be expressed in a response that concomitantly required the function of TH cells. Moreover, since it has previously been suggested that B cells can be directly activated by antigen in the presence of T cell-derived factors (16), there was the possibility that such T cell products might be capable of bypassing or overcoming any MHC recognition requirement for the activation of B cells. In the present report, conditions were first established in which primary antibody responses to limiting concentrations of TNP- 1 Abbreviations used in this paper: ATS, anti-thymocyte serum; C, complement; Con A, concanavalin A; IL-2, interleukin 2; KLH, keyhole limpet hemocyanin; MHC, major histocompatibility complex; MLR, mixed lymphocyte response; PFC, plaque-forming cell; RAMB, rabbit anti-mouse brain serum; SAC, spleen adherent cells; SRBC, sheep erythrocytes; TD, T dependent; (T,G)-A--L, poly-L-(Tyr,Glu)-poly- D,L-Ala--poly-u-Lys;TH, T helper; TI, T independent. 486 J. Exp. MEo. © The RockefellerUniversity Press • 0022-1007/83/02/0486/16 $1.00 Volume 157 February 1983 486-501 HODES ET AL. 487 re shown to be highly T cell dependent (TD). Under these conditions, it was demonstrated that TH cell function did require Tn cell recognition of accessory cell MHC determinants but did not require Tn cell recognition of B cell MHC determi- nants. However, Tn cell activation of TNP-Ficoll-responsive chimeric B lymphocytes still required B cell recognition of self-MHC determinants expressed by accessory ceils. Thus, these findings demonstrate the existence of a novel cell interaction pathway in which both TNP-Ficoll-reactive B cells and TH cells express requirements for MHC-restricted self-recognition of accessory ceils. Materials and Methods Animals. C57BL/10 (B10), B10.A, B10.BR, (B10 × B10.A)F1, (B10 × B10.BR)F1, and (C57BL/6 × A/J)Fx (B6AF1) mice were obtained from The Jackson Laboratory, Bar Harbor, ME. B10.A(2R) mice were provided by Dr. David Sachs, National Institutes of Health (NIH), and [B10.A × B10.A(2R)]F1 mice were provided by Dr. Gene Shearer, NIH. Radiation Bone Marrow Chimeras. Chimeras were prepared as previously described (5). 12-15 × 106 T cell-depleted donor bone marrow cells were injected intravenously into 950-rad- irradiated recipients and rested for 8-24 wk before use. Chimeric spleen cell populations were routinely H-2 typed by indirect immunofluorescence and were uniformly of donor origin without detectable (<5%) host cells. These populations were also tested for proliferative responses in mixed lymphocyte response (MLR) and were found to be unresponsive to host- or donor-type stimulating cells but responsive to third-party allogeneic stimulators. Antigens. TNP-Ficoll was prepared as previously described (17). Sheep erythrocytes (SRBC) used as antigen were obtained from a single sheep (1245) maintained at the NIH Large Animal Holding Facility, Poolesville, MD. Antisera. Cytotoxic (B10.A × A/J) anti-B10 serum was generously provided by Dr. David Sachs and had cytotoxic titers of 1:128 against B 10 spleen cells, 1:32 against B 10.A(2R), and was without significant activity against B10.A target cells. Monoclonal 11-4.1 culture super- natant was used as a cytotoxic anti-Kk reagent with a cytotoxic titer of 1:64 against B10.BR spleen cells (18). For elimination of Kk-bearing cells, this reagent was used in excess at a concentration of 1:2. Cell Preparations. Sterile spleen cell suspensions and fractionated subpopulations of T cells, B cells, and accessory cells were prepared as described previously (19). T Cells. Nylon-nonadherent spleen cells were used as a source of enriched T cells (19). B Plus Accessory Cells. T cell-depleted (B plus accessory) cells were routinely prepared by treatment of spleen cells with cytotoxic monoclonal anti-Thy-1.2 plus complement (C) (16). In selected experiments, more exhaustive depletion was carried out by in vivo treatment of mice with 0.5 ml of a 1: 10 dilution of rabbit anti-mouse thymocyte serum (ATS) (M. A. Bioproducts, Walkersville, MD), followed by sequential in vitro treatment with monoclonal anti-Thy-l.2 plus C and anti-Lyt-l.2 (New England Nuclear, Boston, MA) plus C. B Cells. B cell populations depleted of both T cells and accessory cells were prepared by first passing spleen cells over Sephadex G-10 columns (19) and then treating the resulting cells with anti-Thy-l.2 plus C. Spleen Adherent Cells (SAC). SAC as a source of accessory cells (19) were prepared by glass adherence of spleen cells, followed by recovery of adherent cells, treatment with a T cell-specific rabbit anti-mouse brain serum (RAMB) (19) plus C, irradiation with 2,000 rad, and overnight culture on a roller drum at 37°C before use. T Cell Supernatants FS6-14.13. The T cell hybridoma FS6-14.13 (FS6) was generously provided by Dr. John Kappler, National Jewish Hospital, Denver, CO (20). To generate supernatant, hybridoma cells were cultured for 24 h with 2.5 #g/ml concanavalin A (Con A) (Miles Laboratories, Inc., Elkhardt, IN). At the end of this culture period, 0.2 M alpha-methyl-D-mannoside (Sigma Chemical Co., St. Louis, MO) was added to prevent the mitogenic effects of residual Con A, and culture supernatant was filtered through a 0.45-/~m filter. 488 SELF-RECOGNITION BY T AND B LYMPHOCYTES SPLEEN SUPERNATANT. Con A supernatant from mouse spleen cells was prepared by culturing BALB/c spleen cells with Con A for 18-20 h as previously described (16). Alpha-methyl-D- mannoside was added as for the preparation of FS6 supernatant. CLONE 16 AND CLONE IA36. Clone 16 is a keyhole limpet hemocyanin (KLH)-specific and I- A b-restricted T cell line of (B6 X C3H)F1 origin (21)g and clone la36 is a poly-t-(Tyr,Glu)-poly- D,L-Ala--poly-t-Lys [(T,G)-A--L]-specific and I-A -restricted T cell line of B6 origin (22). Supernatants were generated by stimulation of each clone with irradiated syngeneic spleen cells and 50/zg/ml of the appropriate antigen for 4 d and were generously provided by Dr. Minoru Shigeta, Dr. Masao Kimoto, and Dr. C. Garrison Fathman, Stanford University. In Vitro Response Cultures. Primary antibody response cultures were carried out under conditions previously described (19). The indicated cell populations, antigen, and soluble factors were cultured in 200-#1 flat-bottomed microtiter wells for 4 d at 37°C in 5% COz-air atmosphere. All cultures were carried out in triplicate. Cells were harvested at the end of the culture period, washed, and assayed for plaque-forming cell (PFC) response. PFC Response. Direct (IgM) anti-SRBC or anti-TNP PFC responses were assayed as previously described (19). When PFC were being analyzed for H-2 type, cells were treated at 5 × 106/ml with a 1:15 dilution of anti-H-2 b reagent at 37°C for 30 min, washed, exposed to a 1:6 dilution of rabbit C (Pel-Freeze Biologicals, Rogers, AR) for 30 min at 37°C, washed twice, and assayed for residual cell number and PFC activity. Results Antibody Responses to Limiting Concentrations of TNP-Ficoll Are T Cell Dependent. Although the generation of antibody responses to TNP-Ficoll has been most exten- sively characterized as being independent of a requirement for T cells (15, 17), recent studies (23, 24) have suggested that under certain experimental conditions, the generation of responses to TNP-Ficoll may be substantially T dependent. To study T cell influences on the activation of TNP-Ficoll-responsive B cells, experiments were carried out to establish conditions in which the T dependence of TNP-Ficoll responses would be clearly apparent. As previously reported, primary in vitro antibody responses to 10-2/zg/ml TNP-Ficoll were relatively T independent, showing little or no effect of T cell depletion when responding B 10 spleen cells were treated with anti-Thy-1.2 plus C (Fig.
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