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There is considerable interest in whether increased investment in science, made by society, pays dividends. Some plausibly argue the increased rate of production of information results in an ossification of the canon. Reports, challenging the canon, fall by the wayside. The field thus becomes increasingly complex, reflecting not so much the reality of nature but how we investigate the subject. I suggest that focusing on and resolving the paradoxes evident within a canon will free the logjam, resulting in more resilient research. Immunology is among the fastest growing of biological sciences and is, I suggest, an appropriate case study. I examine the commonly accepted frameworks employed over the last three decades to address two major, related immunological questions: what determines whether antigen activates or inactivates CD4 T cells, and so whether immune responses are initiated or this potential ablated; secondly, what determines the Th subset to which the activated Th cells belong, thus determining the class of immunity generated. I show there are major paradoxes within these frameworks, neglected for decades. I propose how research focused on resolving paradoxes can be better fostered, and so support the evolution of the canon. This perspective is pertinent in facing critical issues on how immune responses are regulated, and to more general issues of both the philosophy of science and of science policy.The last section is in response to questions and comments of the reviewers. It brings together several considerations to express my view: the same frameworks, formulated in response to the two questions, are useful in understanding the regulation of the immune response against model antigens, against self and foreign antigens, those of tumors and of pathogens.

Essential to much medical progress (for example, preventing AIDS, tuberculosis and cancer) is understanding how the class of immunity is controlled. Most envisage that pathogen- or danger-associated signals are critical. Many classical observations, particularly on the variables of immunization affecting the class of immunity generated, are paradoxical under this dominant view, and are therefore neglected. Among these is the role of antigen dose. Plausible strategies to prevent and treat AIDS, cancer and tuberculosis are based on such neglected observations. Many suggest that the information overload stultifies the canon, inhibiting progress. I illustrate here that seeking and resolving paradoxes can provide a different perspective from that of the dominant canon, opening vistas that address major issues pertinent to world health.

Koch attempted to treat tuberculosis in the late 1800s by administering an antigenic extract derived from the pathogen to patients. He hoped to bolster the patient’s protective immunity. The treatment had diverse results. In some, it improved the patient’s condition and in others led to a worsening state and even to death. Koch stopped giving his experimental treatment. I consider here three issues pertinent to realizing Koch’s vision. Rational immunotherapy requires a knowledge of what constitutes protective immunity; secondly, how on-going immune responses are regulated, so the patient’s immunity can be modulated to become optimally protective; thirdly, a simple methodology by which treatment might be realized. I deliberately cast my account in simple terms to transcend barriers due to specialization. The proposed immunotherapeutic treatment, if realizable, would significantly contribute to overcoming problems of treatment posed by antibiotic resistance of the pathogen.

I present here a new model for the primary activation of precursor helper T cells. Observations demonstrate that the immune system learns not to respond to extrathymic, organ-specific self-antigens because of their early appearance in development. The immune system thus discriminates between peripheral self-antigens and foreign antigens and, when mature, usually makes an immune response against only the latter. Contemporary models for the activation and inactivation of T helper (Th) function do not account for such discrimination. The model proposed here is consistent with contemporary findings and incorporates a mechanism of peripheral self-nonself discrimination.

Rational vaccination against and immunotherapy of any infectious disease requires knowledge of how protective and non-protective immune responses differ, and how immune responses are regulated, so their nature can be controlled. Strong Th1 responses are likely protective against M tuberculosis. Understanding how immune class regulation is achieved is pertinent to both vaccination and treatment. I argue that variables of infection, other than PAMPs, primarily determine the class of immunity generated. The alternative, non-PAMP framework I favour, allows me to propose strategies to achieve efficacious vaccination, transcending host and pathogen genetic variability, to prevent tuberculosis, and personalised protocols to treat disease.

Immunologic self-tolerance involves signals from co-inhibitory receptors. Several T cell co-inhibitors, including PD-1, are expressed upon activation, whereas CD5 and BTLA are expressed constitutively. The relationship between constitutively expressed co-inhibitors and when they are needed is unknown. Deletion of Btla demonstrated BTLA regulates CD5 expression. Loss of BTLA signals, but not signalling by its ligand, HVEM, leads to increased CD5 expression. Higher CD5 expression set during thymic selection is associated with increased self-recognition, suggesting that BTLA might be needed early to establish self-tolerance. We found that BTLA and PD-1 were needed post-thymic selection in recent thymic emigrants (RTE). RTE lacking BTLA caused a CD4 T cell and MHC class II dependent multi-organ autoimmune disease. Together, our findings identify a negative regulatory pathway between two constitutively expressed co-inhibitors, calibrating their expression. Expression of constitutive and induced co-inhibitory receptors is needed early to establish tolerance in the periphery for RTE.

Different frameworks, which are currently employed to understand how immune responses are regulated, can account for different observations reported in the classical literature. I have argued that the predominant frameworks, employed over the last two/three decades to analyze the circumstances that determine whether an immune response is generated or this potential is ablated, and that determine the class of immunity an antigen induces, are inconsistent with diverse classical observations. These observations are “paradoxical” within the context of these frameworks and, consequently, tend to be ignored by most contemporary researchers. One such observation is that low and high doses of diverse types of antigen result, respectively, in cell-mediated and IgG antibody responses. I suggest these paradoxes render these frameworks implausible. An alternative framework, The Threshold Hypothesis, accounts for the paradoxical observations. Some frameworks are judged more plausible when found to be valuable in understanding findings in fields beyond their original compass. I explore here how the Threshold Hypothesis, initially based on studies with chemically well-defined and “simple antigens”, most often a purified protein, can nevertheless shed light on diverse classical and more recent observations in the fields of immunity against cancer and against infectious agents, thus revealing common, immune mechanisms. Most cancers and some pathogens are best contained by cell-mediated immunity. The success of the Threshold Hypothesis has encouraged me to employ it as a basis for proposing strategies to prevent and to treat cancer and those infectious diseases caused by pathogens best contained by a cell-mediated attack.

We show that the in vivo generation of cytokine-producing CD4 T cells specific for a given major histocompatibility class-II (MHCII)-binding peptide of hen egg lysozyme (HEL) is facilitated when mice are immunized with splenic antigen presenting cells (APC) pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generation of peptide-specific effector CD4 T cells requires that the same splenic APC be pulsed with both peptides. Pulsed B cells, but not pulsed dendritic cells (DCs), can mediate CD4 T cell cooperation, which can be blocked by disrupting OX40-OX40L (CD134-CD252) interactions. In addition, the generation of HEL peptide-specific CD4 T cell memory is greater when mice are primed with B cells pulsed with the two peptides than with B cells pulsed with the HEL- peptide alone. Based on our findings, we suggest CD4 T cell cooperation is important for vaccine design, underlies the phenomenon of \"epitope-spreading\" seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation.

Observations show that humans and animals respond immunologically to most cancers. Why does the immune system then fail to control cancer? We argue from the literature that there is a commonality in the regulation of responses against most murine tumors, and that a major mechanism of escape may be deviation of an effective Th1, cytotoxic T lymphocyte response to a less effective response with a Th2 component. We examined this hypothesis with two well-studied murine tumors. We found, following primary tumor implantation, that resistance correlates with Th1 responses and IgG2a antibody production and progression with mixed Th1/Th2 responses and production of IgG1 and IgG2a antibodies. Resistance is associated with a modulation of the anti-tumor response towards the Th1 pole in both systems. We conclude that the immune responses against these two tumors are in accord with our hypothesis, and argue that this is likely to be true of many human and murine tumors. The correlation of IgG isotype of anti-tumor antibody with the Th1/Th2 nature of the anti-tumor response readily allows one to longitudinally monitor the changing nature of the anti-tumor response. We suggest that such monitoring can guide immunotherapy to maximize the effectiveness of the host’s immune response against cancer.

Evidence suggesting that the goal of immunization to prevent or control HIV infection should be activation of the cell-mediated, rather than the antibody-mediated, arm of the immune system is presented.