NK‐cell exhaustion, B‐cell exhaustion and T‐cell exhaustion—the differences and similarities

Abstract

T-cell exhaustion has been extensively researched, compared with B-cell exhaustion and NK-cell exhaustion, which have received considerably less attention; and there is less of a consensus on the precise definitions of NK-cell and B-cell exhaustion. NKcell exhaustion, B-cell exhaustion and T-cell exhaustion are examples of lymphocyte exhaustion, and they have several differences and similarities. Lymphocyte exhaustion is also frequently confused with anergy, cellular senescence and suppression, because these conditions can have significant overlapping similarities with exhaustion. An additional source of confusion is due to the fact that lymphocyte exhaustion is not a binary state, but instead has a spectrum of severity induced by different levels and duration of continuous antigenic stimulation. Concurrent multiple types of lymphocyte exhaustion are possible, and this situation is herein called poly-lymphocyte exhaustion. Poly-lymphocyte exhaustion for the same cancer or pathogen would be especially dangerous. As there are significant advantages for a pathogen by inducing poly-lymphocyte exhaustion in an immune system, there are pathogens with an evolved capability to induce poly-lymphocyte exhaustion. These pathogens may include certain manipulative viruses, bacteria, fungi and protozoan parasites.

Concurrent infections of cells by two pathogens can enable a reactivation of the first pathogen and the second pathogen's accelerated T-cell exhaustion

“…A long duration of lymphocyte exhaustion for T-cells and NK-cells was also seen in COVID-19 survivors, even several weeks post-infection [ 42 ]. Such multiple lymphocyte exhaustions could be a major causational factor for the COVID-19 post-infection symptoms collectively called Long COVID [ 42 , 51 ].…”

ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models

“…1B, NK cell activation status correlates with prognosis in CLDN18.2-expressing gastric carcinomas, and, more specifically, a low level of NK cell activation portends a poor outcome in CLDN18.2-positive gastric cancers. Indeed, gastric tumors can evade from NK cell by inducing immunologically cold tumor microenvironment (26)(27)(28). Thus, we designed ZL-1211 to induce NK cell activation, which potentially improves treatment outcomes in patients with gastric tumor.…”

A Standardized Metric to Enhance Clinical Trial Design and Outcome Interpretation in Type 1 Diabetes

“…This observation is likely accounted for in part by a moderate association between treatment-induced exhausted T cells and age (Figure 7C). As previously noted, age is one of two key variables in the QR metric; age is also known to be important in defining setpoints and responsiveness for many immune cell populations (recently reviewed in [24][25][26][27] ). This novel analysis implies that therapy-induced exhaustion of T cells unveils mechanistic insights about age itself, which may or may not be causally related to a particular therapy, but is important to our understanding of the role age plays in disease progression and response to therapy.…”