The immune exhaustion paradox: activated functionality during chronic bacterial infections

Abstract

Co-inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), known as immune checkpoints, regulate the activity of T and myeloid cells during chronic viral infections and are well-established for their roles in cancer therapy. However, their involvement in chronic bacterial infections, particularly those caused by pathogens endemic to developing countries, such as Mycobacterium tuberculosis (Mtb), remains incompletely understood.

Cytokine microenvironment determines the expression of co-inhibitory molecules in tuberculosis: Results indicate that the cytokine IL-12, in the presence of Mtb antigens, can enhance the expression of co-inhibitory molecules while preserving the effector and memory phenotypes of CD4+ T cells.

Intersection of immune checkpoint inhibitors` role in cancer therapy and active tuberculosis: As discussed, co-inhibitory molecules` expression is crucial for effectively controlling inflammation during chronic bacterial infections. It has been suggested that monoclonal antibodies (mAbs) developed for cancer immunotherapy, known as immune checkpoint inhibitors (ICIs), may be associated with the reactivation of latent tuberculosis (LTB), though this occurrence has been rarely reported.

Immune checkpoint molecules function as a “brake” to protect the host from the pathological effects of the immune response during chronic bacterial infections, which contrasts with the concept of exhaustion in the context of cancer. This means cells expressing co-inhibitory molecules on their surface can be paradoxically activated, as suggested in this review.