The Adaptation Model of Immunity: Signal IV Matters Most in Determining the Functional Outcomes of Immune Responses

Abstract

Current research in immunology and immunotherapy is fully influenced by the self–nonself model of immunity. This theoretical model suggests that alloreactivity results in graft rejection, whereas tolerance toward self-antigens expressed by malignant cells facilitates cancer development. Similarly, breakage of immunological tolerance toward self-antigens results in autoimmune diseases. Accordingly, immune suppression is recommended for the management of autoimmune diseases, allergy, and organ transplantation, whereas immune inducers are used for the treatment of cancers. Although the danger model, the discontinuity model, and the adaptation model are proposed for a better understanding of the immune system, the self–nonself model continues to dominate the field. Nevertheless, a cure for these human diseases remains elusive. This essay discusses current theoretical models of immunity, as well as their impacts and limitations, and expands on the adaptation model of immunity to galvanize a new direction for the treatment of autoimmune diseases, organ transplantation, and cancer.

Effective anti-tumor immune responses are orchestrated by immune cell partnership network that functions through tissue homeostatic pathways, not direct cytotoxicity

“…Such tissue-based activation of the immune response is evident from the presence of tissue-resident T memory cells (Trm) 54 which can be explained by the quantum model of T cell activation recently proposed by the last author 55 . Also, the primary function of immune responses has been proposed to be participating in homeostasis of their target cells [56][57][58][59][60][61] . This homeostatic function can explain the observations on inability of auto-reactive T cells to induce autoimmune pancreatitis following adoptive transfer of OVA-specific T cells that recognized and became activated by OVA-expressing pancreas 62 .…”

The quantum model of T‐cell activation: Revisiting immune response theories

“…In fact, these models are predicted upon the assumption that the main role of the immune system is to safeguard the host against invading pathogens and diseases. However, following an extensive review of the existing literature, we have recently posited that the immune system's principal function lies in its participation in maintaining tissue homeostasis 17,18 . This function is orchestrated by activated and effector immune cells that support haemostasis of their target cells, which differs from tissue homeostasis through checks and balances of immune cells or Newtonian action and reaction of effector and regulatory cells 19 .…”

“…However, following an extensive review of the existing literature, we have recently posited that the immune system's principal function lies in its participation in maintaining tissue homeostasis. 17,18 This function is orchestrated by activated and effector immune cells that support haemostasis of their target cells, which differs from tissue homeostasis through checks and balances of immune cells or Newtonian action and reaction of effector and regulatory cells. 19 This is exemplified by the selective survival of self-reactive T cells during thymic positive selection.…”

“…Consequently, these self-reactive T cells are capable of activation by self-antigens, even in the absence of infection, damage or disintegration, as reviewed recently. 17 To this end, myelin basic protein (MBP)-specific T cells have been detected in the circulation of healthy individuals without causing multiple sclerosis (MS). 20 Also, meningeal T cells producing IFN-γ have been shown to play a crucial role in preventing aberrant hyper-excitability within the central nervous system (CNS).…”

“…23 Consequently, alterations in target tissues that result in an intolerance of an ongoing immune response can lead to autoimmune diseases, effectively characterized as immune intolerance. 17,18 Recently, the first author proposed the term 'immune intolerance' as a more fitting nomenclature for the understanding of autoimmune diseases. This term posits that a continuous immune response maintains communication with somatic cells through adaptation receptors (AdRs) and adaptation ligands (AdLs), as well as coreceptors (signal IV), to facilitate cell growth and homeostasis (Table 1).…”