H-2-controlled suppression of T cell response to lactate dehydrogenase B. Characterization of the lactate dehydrogenase B suppressor pathway.

Abstract

Over the past few years, considerable progress has been made in the identification of regulatory T cell pathways and factors that act as mediators between T cell subsets involved in these pathways (1-3). However, at least two important aspects of regulation of the immune response have remained largely unexplored. One of them is the role of antigen presentation and of major histocompatibility complex (MHC)1 restriction in the activation of suppressor T (Ts) cells. From the paucity of reports on MHC restriction of Ts sets (4-8), one would conclude that MHC-restricted antigen presentation is not essential for the activation of most suppressor pathways. This view gains support from the demonstrated high affinity of some Ts cells for free antigen (9-11). It is, however, equally possible that the uncertainties about MHC restriction in Ts systems reflect the absence of an appropriate experimental model in which the interaction of Ts cells with antigen-presenting cells (APC) could be explored.The second aspect that appears to be neglected is the mechanism of interaction between Ts effector cells and their targets. The mode of action of suppressor-effector factors is largely unknown (12)(13)(14), and, to our knowledge, there is only one report in the literature that bears on the direct interaction between Ts cells and T helper (Th) cells (15).Our recent work on the proliferative T cell response to lactate dehydrogenase B (LDHB) has provided a system suitable to study the questions outlined above. We have demonstrated (6-18) that most H-2 haplotypes respond to LDHB and that the T cell proliferation in all responder haplotypes is restricted by the molecule controlled by the A~ and A~ loci in the I-A region of H-2 (A [A~Aa] molecules). The proliferating cells are most likely Th cells because their genetic control is almost identical with that of antibody production to LDHB (16,19). Nonresponder haplotypes to LDHB include virtually all strains that carry the k allele at the E~ and E~ loci of the H-2 complex. However, nonresponsiveness can be reversed by in vivo or in vitro administration of monoclonal antibodies against the molecule controlled by the E~ locus in the I-A and * Supported in part by grant Wa 139/No/A.I5 from the Deutsche Forschungsgemeinschaft. 1 Abbreviations used in this paper: A molecule, controlled by the A~ and A• loci in the I-A region of H-2; APC, antigen-presenting cell; BudR, 5-bromo-2'-deoxyuridine; E molecule, controlled by the E B locus in the I-A and the E~ locus in the I-E region of H-2; GA, poly(Glue'°Ala4°) ; GAT, poly (Glu6°Alaa°Tyrl°); GT, poly (GluS°TyrS°); KLH, keyhole limpet hemocyanin; LDHB, lactate dehydrogenase B; MHC, major histocompatibility complex; SI, stimulation index; SRBC, sheep erythrocytes; Th, T helper cell; Ts, T suppressor cell; Tsel T suppressor effector; Tsi, T suppressor inducer. 822J. ExP. MED.

Epitope-Specific Regulation of the Antibody Response against Alpha-Lactalbumins in the Mouse

“…The third mechanism for the specific unrespon siveness is due to the induction of Ts cells by the anti gen [14][15][16][17][18][19] [25], Suppressor epitopes presented by LR class II molecules induce LR-haplotype-restricted Ts cells which suppress only the LRhaplotype-restricted but not HR-haplotype-restricted F, Th cell subsets, although the existence of Ts cells in F| mice is not directly demonstrated in the present study. This possibility has been examined and dis cussed in several other reports [8,26,27], where re sponsiveness to Ir-gene-controlled antigens was dom inant.…”

“…It has been proposed that the ability of class II MHC product to present an tigenic fragment determines the responsiveness of the individuals to the given antigen [9][10][11][12][13]. The other pos sibility is the preferential induction of suppressor T cells that prevents the response to the antigen [14][15][16][17][18][19]. In the present study, we demonstrated that the re sponse to ALA is under the control of H-2-linked Ir gene and that the unresponsiveness to ALA is due to the induction of specific suppressor T cells in certain mouse strains.…”

Regulatory mechanisms in immune responses to heterologous insulins. II. Suppressor T cell activation associated with nonresponsiveness in H-2b mice.

“…An immune response to pork insulin is observed only after amputation of the pork insulin-specific suppressor limb. A similar situation was described by Baxevanis and associate (8) in which T cells from primed nonresponder strains developed proliferative responses to LDHa in vitro only after addition of antibodies that specifically blocked the suppressor pathway or after removal of Lyt-2-bearing Ts cells. Collectively, these studies suggest that H-2-linked Ir gene control of immune responses is the net result of the stimulation of a variety of T cell subsets and that "holes" in the functional repertoire of Th cells can be mediated by the dominant activity of Ts cells.…”

<i>Candida albican</i><i>s</i> Mannan-Specific, Delayed Hypersensitivity Down-Regulatory CD8+ Cells Are Genetically Restricted Effectors and Their Production Requires CD4 and l-A Expression

“…Although H-2 restriction of DH has been illustrated in vivo in a transfer system similar to I-A+ and CD4+ Cells Required for Mannan Suppression that employed here for the demonstration of suppressor ac tivity [26], we know of no other papers in which FI-2 re striction of down-regulatory activity has been illustrated in vivo by lymphoid transfer experiments. Clearly, H-2 restric tion of various activities associated with 13 cell suppression has been illustrated in vitro with suppressor cells generated in vivo [48][49][50], but the genetically restricted activity was involved in the effector phase of the response rather than the inductive phase. Genetically restricted activities involving contact sensitivity have also been described [51], but in this case the need for compatible accessory cells was investigat ed at the level of the third-order suppressor cell, not the firstorder inducer-suppressor cell.…”