Proc. Natl. Acad. Sci. USA Vol. 89, pp. 10365-10369, November 1992 Immunology Adaptive cellular interactions in the immune system: The tunable activation threshold and the significance of subthreshold responses (context dis nation/autoreavity/meanr/m oy units) Zvi GROSSMAN*t AND WILLIAM E. PAULt *Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and tLaboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Contributed by William E. Paul, July 21, 1992 ABSTRACT A major challenge for Immunologists is to (iv) Memory: Static or dynamic? Memory cells show signs explain how the immune system adjusts its responses to the of activation but undergo limited division before challenge. microenvironmental context in which antigens are roi. Their inherent longevity has been questioned, but whether We propose that lymphocytes achieve this by tuning and they require continued stimulation by residual antigen re- updating their responsiveness to rcurrent signals. In partic- mains unresolved (6). ular, cellular anergy in vivo is a dynamic state in which the (v) The in vivo/in vitro dichotomy. Recent experiments in threshold for a stereotypic mode of activation has been ele- which animals are rendered deficient in specific genes have vated. Anergy is associated with other formsofcellular activity, provided some surprises. Interleukins 2- and 4-deficient mice not paralysis. Cells engaged in such subthreshold interactions appear surprisingly normal (7, 8). In transgenic mice over- mediate functions such as maintenance ofimmu l mem- expressing major histocompatibility complex (MHC) class II ory and control of infections. In such interactions, patterns of antigens, immune responses were largely unaffected and signals are recognized and ciasied and evoke selective re- there was no indication ofuncontrolled lymphoproliferation, sponses. The robust mechanis proposed for segregation of immunodeficiency, or autoimmunity (9). Finally, anergy as suprathreshold and subthreshold immune responses allows assayed in vitro correlated in some cases in vivo with memory lymphocytes to use recognition of self-antigens in executing (10) and activation (11) rather than tolerance. physiological functions. Autoreactivity is allowed where it is (vi) Complexity ofsignaling. Many peptide factors, includ- dissociated from uncontrolled on. ing lymphokines, are multifunctional, have a broad range of target cells, and the activity of one peptide in a single cell Despite the major contributions of molecular and cellular depends on the other signal molecules present (12). More- immunology, the physiological rules of immunity are poorly over, the existence of bidirectional communication between understood (1). Consequently, progress achieved in autoim- the immune system and the hemopoietic and neuroendocrine mune diseases, transplantation tolerance, allergy, and systems is now established. There is a growing schism (13) chronic infectious diseases has been limited (2). Some of the between the broadening scope of physiologic connections unresolved issues are listed below. and the traditional concept of antigen-oriented lymphocytes (i) The enigma of autoreactivity and anergy. There is that function as the specialized members of a stereotypical benign autoreactivity in healthy individuals, and the presence defense system. Why should lymphocytes, with their clonally of autoreactive lymphocytes is pronounced during infection distributed receptors for antigens, require so rich and so (3). Therefore, self/nonself discrimination may be much intricate communication among themselves and with other more complex than the simple failure of competent lympho- cells? cytes to recognize self-antigens. (vii) How does the immune system discriminate antigens by Cellular unresponsiveness (anergy) has been proposed as a context? There is a rich repertoire of cellular responses, major self-tolerance mechanism in addition to clonal deletion mediated by different molecules and their combinations, (4, 20, 27, 29). Natural autoreactivity could be ascribed to ranging from direct killing of the antigen-bearing cells to the cells that have escaped both mechanisms. However, the activation, or inactivation, of these cells and/or other lym- orderly nature of autoreactivity needs to be explained: the phocytes and accessory cells. The selection of a particular targets of both benign autoreactivity and autoimmunity in response depends not only on the nature and quantity of the different individuals are not random, but restricted and antigen, but also on the tissue and site of encounter and on predictable (5). The very concept ofanergy as a self-tolerance other cofactors. An illustration is provided by the striking mechanism is problematic: one might expect that the number differences in the response to the antigens ofMycobacterium of autoreactive cells, potentially the cause of autoimmunity, leprae in tuberculoid and lepromatous leprosy (14). The should be reduced to a minimum. immune system appears to recognize and classify different (ii) Multiclonal activity. The extensive involvement in patterns ofsignals, even within the same tissue. The respond- specific immune responses of clones that lack receptors for ing cells, in turn, differ in the pattern of cytokines they the immunogen has not been satisfactorily explained. It is secrete and in the effector functions they execute, both often attributed to so-called bystander effects, to progression individually and collectively. The explanation, in terms ofthe of idiotypic signals along a network, or to other pathological properties of individual cells, of how the immune system effects. adjusts its response to the environmental context in which (iii) Suppression. Attempts to formulate the principles antigen is recognized is a major challenge. underlying the interplay of suppression and help have been The unresolved questions listed above are taken as indi- limited. The issue ofthe controversial suppressor cells is still cations that currently accepted hypotheses may be suscep- confusing. tible to modification. The following analysis is an attempt to The publication costs ofthis article were defrayed in part by page charge Abbreviations: TAT, tunable activation threshold; TCR, T-cell re- payment. This article must therefore be hereby marked "advertisement" ceptor; APC, antigen presenting cell; MHC, major histocompatibility in accordance with 18 U.S.C. §1734 solely to indicate this fact. complex. 10365 Downloaded by guest on October 2, 2021 10366 Immunology: Grossman and Paul Proc. Natl. Acad Sci. USA 89 (1992) examine the logical consequences of varying the presuppo- The Tunable Activation Threshold (TAT) Model sitions about the nature of immunological functions by way of deductive reasoning. Let us assume that the direct effect on a cell of an external stimulus is changing the metabolic state of the cell in a way The Adaptable Lymphocyte Hypothesis: Presuppositions that can be expressed in quantitative terms. The metabolic change will be referred to as excitation and it is assumed, for Infection can, in theory, sneak through classical immunolog- simplicity, that there is a (positive) scalar measure, termed ical surveillance if its progression is gradual (15-17). Typical excitation level, of this excitation. of many real-life infections is a fast initial increase in antigen Two classes of models may be proposed: balance-of- concentration. It is this kinetic aspect that leads, partly due growth models (15-17) and cell-tuning models. Both regard to time delays along the feedback loops that regulate the the lymphocyte as a multistate system with alternative state immune response at the cell population level, to an overshoot transition pathways, e.g., (i) maintenance: rest -) excitation in the number of effectors and to effective elimination of the rest; (ii) self-renewal: rest -+ excitation proliferation antigen (15-17). (=self-renewal) -+ rest; (iii) activation: rest excitation On the other hand, a destructive immune response aimed proliferation (=amplification) -* differentiation. at the elimination of all antigen-bearing cells may be unde- Only the third process is defined as activation: induction of sirable in the case ofa slow but widespread infection. In such proliferation and (stepwise) differentiation of at least some cases of chronic infection, or residual infection (when the progeny. Balance-of-growth models are concerned with the initial growth burst of infectious agent has been controlled), balance between processes ii and iii, whereas cell-tuning different modes of resistance are required in which patterns models focus on i and ii and their dynamic segregation from of signals are recognized and classified and selective re- iii. sponses are evoked. We shall loosely refer to this class of While balance-of-growth models emphasize Darwinian- responses as environment regulated to underscore their type selection and the proliferation-differentiation interplay, adaptability. These responses are characterized by a variety more recent evidence has indicated that cell viability can be oflocally applied effector and regulatory functions and a fine promoted independently of growth (19) and that processes discrimination of antigenic stimuli based on the associated such as thymic selection of T lymphocytes, during a critical signals (the context). The functions could be implemented by phase, or memory cell maintenance do not involve