Abstract
T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.
Highlights
T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues
Thymocyte development and peripheral T cell differentiation depend on CCT8 expression
Fewer phenotypically and functionally mature single positive CD4+ (SP4) and SPCD8 thymocytes were detected at a late stage of their development (Fig. 1c, j, k and Supplementary Fig. 1) and the frequencies of thymic and recirculating regulatory T cells (Treg) were likewise reduced (Fig. 1l, m)
Summary
T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems These findings demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity. The competence of T cells to respond adequately to antigenic challenges is inextricably linked to de novo protein expression and a change in the cell’s protein homeostasis Under optimal conditions, this process relies on a complex network of interconnected, dynamic systems that control protein biosynthesis, folding, translocation, assembly, disassembly and clearance[2]. Cell stress and other physiological demands on the cell’s proteome can result in challenges where nascent and metastable proteins are misfolded and, as a result, aggregateentrapped polypeptides are formed These conformational changes challenge, as toxic intermediates, a cell’s functions and may impair its survival. Each of the rings is composed of homologous, yet distinct 60 kDa subunits (α, β, γ, δ, ε, ζ, η and θ)[7]; CCTs recognize, bind and globally enclose protein substrates of up to ~60 kDa to allow their folding over several cycles
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