J. F. A. P. Miller

Help for cytotoxic-T-cell responses is mediated by CD40 signalling

Cytotoxic T lymphocytes (CTLs) which carry the CD8 antigen recognize antigens that are presented on target cells by the class I major histocompatibility complex. CTLs are responsible for the killing of antigen-bearing target cells, such as virus-infected cells. Although CTL effectors can act alone when killing target cells, their differentiation from naive CD8-positive T cells is often dependent on ‘help’ from CD4-positive helper T (TH) cells. Furthermore, for effective CTL priming, this help must be provided in a cognate manner, such that both the TH cell and the CTL recognize antigen on the same antigen-presenting cell,. One explanation for this requirement is that TH cells are needed to convert the antigen-presenting cell into a cell that is fully competent to prime CTL. Here we show that signalling through CD40 on the antigen-presenting cells can replace the requirement for TH cells, indicating that T-cell ‘help’, at least for generation of CTLs by cross-priming, is mediated by signalling through CD40 on the antigen-presenting cell.

Induction of Autoimmune Diabetes by Oral Administration of Autoantigen

An antigen administered orally can induce immunological tolerance to a subsequent challenge with the same antigen. Evidence has been provided for the efficacy of this approach in the treatment of human autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. However, oral administration of autoantigen in mice was found to induce a cytotoxic T lymphocyte response that could lead to the onset of autoimmune diabetes. Thus, feeding autoantigen can cause autoimmunity, which suggests that caution should be used when applying this approach to the treatment of human autoimmune diseases.

Cross-presentation: a general mechanism for CTL immunity and tolerance

Abstract MHC class I-restricted presentation is usually associated with the processing of endogenous antigens. However, this restriction element can present antigens that do not originate within the presenting cells. Here, Francis Carbone and colleagues describe how such cross-presentation is critical for cytotoxic T-cell surveillance of peripheral antigens, both self and foreign, located outside the secondary lymphoid compartment.

Antigen-induced selective recruitment of circulating lymphocytes

Abstract Thoracic duct lymphocytes obtained from mice 1–2 days after the injection of sheep erythrocytes and injected into thymectomized, irradiated, marrow-protected syngeneic hosts were deficient in adoptively transferring immune reactivity to sheep erythrocytes but normal with respect to horse erythrocytes. Cells collected at 3 days had normal reactivity, but cells collected at 5 days allowed their hosts to produce an enhanced response to sheep erythrocytes and a somewhat depressed response to horse erythrocytes. Thoracic duct lymphocytes obtained from CBA mice 2 days after injection of CBA × C57BL)F 1 spleen cells produced splenomegaly in newborn (CBA × BALB/c)F 1 mice but not in (CBA × C57BL) F 1 recipients. When obtained 5 days after injection, they caused an increase in the splenic index of the (CBA × C57BL) F 1 recipients significantly above that given by control lymphocytes from saline-injected donors. These results are interpreted in terms of a selective recruitment from the circulation of specific antigen-sensitive cells, occurring soon after antigen administration and followed in turn by a rapid reentry of such cells into the pool in an increased proportion.

Characterization of the ovalbumin-specific TCR transgenic line OT-I: MHC elements for positive and negative selection

The present report provides the first extensive characterization of the OT‐I TCR transgenic line, which produces MHC class I‐restricted, ovalbumin‐specific, CD8+ T cells (OT‐I cells). These cells are shown to be positively selected in vivo in H‐2b C57BL/6 mice and in bm5 mice, which express the Kbm5 mutant molecule. In contrast, OT‐I cells were not selected by mutant Kb molecules in bm1, bm3, bm8, bm10, bm11 or bm23 mice. Interestingly, however, when positive selection was examined in vitro in foetal thymic organ culture (FTOC), bm1 and bm8 were still poorly selective, but the bm3 haplotype now selected as efficiently as B6. The ability to select in vitro correlated with the capacity to present the ovalbumin (OVA) peptide to OT‐I cells, as measured by induction of an OVA‐specific proliferative response. These results suggest that a lower affinity TCR:MHC interaction may be necessary for positive selection in FTOC compared with selection in situ.

Thymic regeneration: teaching an old immune system new tricks

Recent studies in mice and humans show that the importance of the thymus extends well beyond the initial seeding of the peripheral T-cell pool. Although peripheral homeostasis can maintain T-cell numbers, the thymus is the major, if not the exclusive, source of new T-cell specificities. With age, thymus atrophy dramatically reduces the export of new T cells and predisposes an individual to impaired T-cell function, reduced T-cell immunity, and increased autoimmunity. Thymus atrophy is also the primary obstacle to restoration of the T-cell pool in the aftermath of HIV treatment or lymphoablative therapies. Here, we review thymus T-cell production, with particular attention to the factors that influence thymocyte export, and examine the impact that recent thymic emigrants have on the peripheral pool. In the future, thymic regeneration might become a feasible and potentially powerful approach to rejuvenating a depleted peripheral T-cell pool.

Mechanisms of tolerance to self

Several mechanisms exist to prevent lymphocytes from reacting against self-antigens. As T cells develop in the thymus and express antigen-specific receptors, those with high-affinity to self-antigens existing within the thymus are deleted. Low-affinity self-reactive T cells and T cells with receptors against antigens not represented intrathymically will mature and join the peripheral T cell pool. They may either ignore self-antigens expressed by tissues unable to activate T cells through a lack of the appropriate costimulator signals, or they may, under certain conditions, be deleted or rendered anergic and unable to respond. Likewise, B cells that express surface Ig receptors with high binding affinity to membrane-bound self-antigens present in the bone marrow will be rescued by receptor editing or will be deleted, whereas those of lower affinity will migrate to the periphery in either an anergic or indifferent state depending on the degree of receptor engagement by antigen. Once there, their ultimate fate is determined by the availability of T cell help.

The discovery of thymus function and of thymus-derived lymphocytes.

Summary: For centuries the thymus remained an enigmatic organ with unknown functions. The first demonstration of its crucial role in establishing the development of a normal immune system was provided in 1961, when it was shown that mice thymectomized immediately after birth had poorly developed lymphoid tissues, impaired immune responses and inordinate susceptibility to intercurrent infections. Although thymus lymphocytes were believed to be immunoincompetent, it was shown in 1967 that they could respond to antigen by proliferating and giving rise to a progeny of cells that could not produce antibody, but enabled other lymphocytes, derived from bone marrow, to differentiate to antibody‐forming cells. This was the first unequivocal demonstration, in mammalian species, of the existence of two major interacting subsets of lymphocytes, T and B cells. It required a re‐evaluation of many immunological phenomena, such as tolerance, memory and autoimmunity, and it was followed by an avalanche of work elucidating many of the mysteries of the immune system.

Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens

Summary: There is now convincing evidence that CD8+ T cells can be activated by professional antigen‐presenting ceils which present antigens derived from non‐lymphoid tissues in association with MHC class I molecules in the draining lymph nodes. This mechanism, referred to as cross‐presentation, enables the immune system to respond to those microorganisms that infect only non‐lymphoid tissues. Consistent with this view, cross‐presentation was found to focus on antigens expressed in high concentrations and those released from dying cells, which can be expected to result from viral infections. Recent evidence, however, demonstrates that high dose self antigens can be cross‐presented constitutively, resulting m the activation of autoreactive CD8+ T cells. This does not lead to auto‐immunity under physiologic conditions, but to CD95‐mediated deletion of the T cells. Cross‐presentation can thus engage a well‐defined pathway of antigen‐induced T‐cell death and purge the immune system of autoreactive CD8+ T cells. Low dose self antigens are not cross‐presented and are consequently ignored. The immune system therefore uses two strategies to avoid CD8+ T‐cell‐mediated autoimmunity in the periphery: deletion of autoreactive CD8+ T cells responding to high dose self antigens and ignorance of self antigens expressed at low concentrations.

Regulation by the H-2 gene complex of delayed type hypersensitivity

Identity at the major histocompatibility complex (MHC) was essential for successful transfer of delayed type hypersensitivity (DTH) in mice. The regions of the MHC involved differed according to the antigen used for sensitization. In the case of fowl gamma globulin (FGG), identity atI-A was necessary, whereas with dinitrofluorobenzene (DNFB), identity at theK, I, orD region was sufficient. These different genetic constraints probably reflect differences in the mechanisms by which antigens are presented to T lymphocytes. Cells from sensitized (CBA×C57BL)F1 mice transferred DTH to FGG into parental-strain mice, but transfer was more effective in C57BL than in CBA with the same cell dose. This phenomenon is governed by the MHC, since there was better transfer intoH-2b than intoH-2k mice, regardless of their backgrounds. It may reflect the activity of an Ir gene-dependent process. Cells of one genotype (e.g., CBA), sensitized in chimeric mice derived from two MHC-incompatible strains (CBA↔C57BL), transferred DTH to both strains. These results do not support the notion that the genetic constraint observed in DTH transfer may be a result of the necessity for sensitized T and stimulator cells to match an identical MHC-coded cell interaction molecule. Rather, they favor the hypothesis that T cells recognize antigen, not as a naked determinant, but in close association with products of genes of the MHC.