Immune Activation: Recognizing Threats

Differentiating self from nonself is a hallmark of the immune response

The immune system is a network of tissues, cells, and signaling molecules that work to protect the body by recognizing and attacking foreign cells, while seeking to minimize the damage to healthy cells.^1,2 This ability to differentiate self (the body’s own normal cells) from nonself (abnormal/foreign cells) is a hallmark of the immune response.^2,3 The capacity of the immune system to recognize self antigens and accept the presence of normal cells is known as self-tolerance.² When self-tolerance fails, it can result in autoimmunity, whereby the immune system may fail to discriminate self from nonself and attack normal cells.⁴

Antigens, small molecules or peptides capable of eliciting an immune response, are a key element in this process of distinguishing self from nonself.¹ Classified as either self or nonself, antigens serve as labels that enable the immune system to distinguish between a normal interaction (self) and an encounter with a foreign threat (nonself).¹ Inactive T cells search for nonself antigens by transiently binding to antigens presented by major histocompatibility complexes (MHCs) on antigen-presenting cells (APCs).⁵ Recognition of nonself antigens activates cytotoxic T cells.¹ Although they originate from normal cells, tumor antigens can be recognized as nonself. Neoantigens, a type of tumor antigen, arise from normal self proteins that have mutated or been modified, making them unique to the tumor and previously undetected by the immune system.^3,6

To prevent autoimmunity, immune cells learn to overlook self antigens both during their maturation (central tolerance) and as they circulate in peripheral tissue (peripheral tolerance).² Most self-reactive T cells are eliminated early in their development; however, peripheral tolerance exists to prevent recognition of self antigens that may not have been encountered during maturation. Immune checkpoint pathway interactions are one mechanism of peripheral tolerance.^2,7

The immune system identifies nonself invaders through both innate and adaptive immunity. The innate immune response is rapid, while the adaptive immune response is not as immediate but can produce a durable response through the development of memory cells, including memory T cells.^1,8 Chronic exposure to nonself antigen can promote the accumulation of memory T cells.⁸ Innate and adaptive immunity are activated through distinct and often complementary mechanisms that deploy different effector cells to attack and destroy abnormal/foreign cells such as cancer.¹