Complement and T Cell Metabolism: Food for Thought

Abstract

The classical complement system is engrained in the mind of scientists and clinicians as a blood-operative key arm of innate immunity, critically required for the protection against invading pathogens. Recent work, however, has defined a novel and unexpected role for an intracellular complement system-the complosome-in the regulation of key metabolic events that underlie peripheral human T cell survival as well as the induction and cessation of their effector functions. This review summarizes the current knowledge about the emerging vital role of the complosome in T cell metabolism and discusses how viewing the evolution of the complement system from an "unconventional" vantage point could logically account for the development of its metabolic activities.

Integrins meet complement: The evolutionary tip of an iceberg orchestrating metabolism and immunity

“…CD46 is absent in rodent somatic tissue in its "modern" form, and a functional homologue that fully recapitulates its activity has not yet been defined (Riley, Kemper, Leung, & Atkinson, 2002;Tsujimura et al, 1998;Yamamoto, Fara, Dasgupta, & Kemper, 2013). We will therefore focus in the following on human T-cells and only succinctly summarize the connection between the complosome and single-cell metabolism as more comprehensive reviews on this subject have recently been published (Hess & Kemper, 2016;West & Kemper, 2019;. Carrillo, 1979;Le Friec et al, 2012).…”

“…Based on the location-driven activity of complement, its functionally important cross-activity with other intracellular danger sensor systems, and the emerging key role for all of these systems in cell physiology, we suggest that complement may have originally appeared in single-cell organisms as an intracellular sensor and rectifier of metabolic stress. With the evolution of into multi-organ organisms-and particularly with the development of a vascular system-complement took a bifurcated path: Part of the original C3 remained functional mostly within cells to control cell physiology, while part of C3 segregated into a secreted form, mostly produced by hepatocytes and assumed the role of the systemic pattern recognition system (Elvington, Liszewski, & Atkinson, 2016;Hess & Kemper, 2016;Kolev & Kemper, 2017;West et al, 2020;West & Kemper, 2019). We suggest that the structure and the posttranslational modifications of intra-and extra-cellular C3 is different: liver-derived C3 is folded into the classically known structure that can generate the opsonin C3b as well as the backbone for C3/C5 convertase formation.…”

Oxytocin’s anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach

“…It induces the proliferation and differentiation of T regulatory 1 cells, which produce large amount of IL10 and inhibit T cell activation. Therefore, reducing CD46 expression may increase T cell activation ( 3 , 30 , 54 , 55 ). Interestingly, while carbetocin’s signature profile was in support of a T cell activation hypothesis, Lopinavir and hydroxychloroquine were not.…”

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

“…Next to its well-known role, it has become evident that intracellular complement plays an important role in homeostasis [reviewed in ( 12 , 13 )]. It has been shown that complement proteins are expressed by a large variety of cells that secrete these proteins into the local environment when needed.…”

“…It has been shown that complement proteins are expressed by a large variety of cells that secrete these proteins into the local environment when needed. Recent studies also indicate that T cells not only express C3 but actually need intracellular C3 activation fragments for their survival ( 12 , 13 ). Next, complement receptor CD46, described in more detail below, has also been identified as an important player in T cell homeostasis ( 14 ).…”