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Elucidation of the selection mechanism of T cells by thymus-specific proteasomes

 Acquired immunity is an elegant system that distinguishes between self and non-self, attacking only non-self. T cells are central to this specific response. Our bodies are protected by maintaining a set of T cells (called a repertoire) that can attack a wide range of pathogens entering the body, while at the same time not attacking our own healthy cells.

Research3e1.jpgFig. 1 The thymus can be divided into two regions, the cortex and medulla. Only cells that pass both positive selection in the cortex and negative selection in the medulla become mature T cells. Individual T cells express only one type of T cell receptor (TCR) on the cell surface. Through interacting with the major histocompatibility complex (MHC) on other cells’ surface, this T cell receptor determines whether to eliminate a cell. An indispensible piece of information for this process is a peptide fragment that is bound to a groove in the MHC and presented to the TCR. By presenting this peptide fragment along with the MHC, it can be determined whether non-self agents have affected self-cells.
In order to respond to foreign pathogens that enter our body, TCRs have an enormous range of variety. T cells differentiate and grow in the thymus, an organ located above the heart. First, random gene reconstruction (the same system that creates diversity in antibodies) creates diverse TCRs on the order of 10 to the xx power. From this ensemble, only T cells with a TCR that does not attack self but has the potential to recognize and attack non-self are selected to create a useful T cell repertoire. This process is carried out through “positive selection” and “negative selection.” Only useful T cells are allowed to survive through selection by cortical thymic epithelial cells (cTEC) (=positive selection), followed by removal of cells that react strongly to self-components through selection by medullary thimic epithelial cells (mTEC) and dendritic cells (DC) (=negative selection).
This positive selection and negative selection are performed by cTEC and mTEC based on the interaction between antigen presentation of self-antigen peptides and the MHC complex with individual T cell TCRs. Cells selected by peptide/MHC class I complex differentiates into CD8+ T cells (killer T cells), while cells selected by peptide/MHC class II complex differentiates into CD4+ T cells (helper T cells). Understanding of the molecular basis for negative selection has progressed with discoveries such as that of the transcription factor AIRE (autoimmune regulator), which makes mTEC express organ-specific antigens, suggesting that even while specific to the thymus, mTEC functioned as a “department store of self-components” and made negative selection effective. On the other hand, much remained unknown about positive selection, and many questioned whether there was a specific pathway for positive selection, or for the necessity of the positive selection process altogether.
Recently, we have discovered a cTEC specific proteasome catalytic subunit β5t, and a “thymoproteasome” which contains β5t as a catalytic subunit. In β5t knockout mice, positive selection of CD8+ T cells was severely impaired with an 80% decrease in number of CD8+ cells, and the remaining limited T cell repertoire was an ineffective repertoire unable to mount a proper immune response (Science 2007, Immunity 2010).

Research3e2.jpgFig. 2 There exists a thymoproteasome which integrates a thymus-specific subunit, b5t. The proteasome is the enzyme responsible for producing MHC class I binding peptides. The proteasome degrades proteins and excretes peptides 3 to 20 amino acids in length. Of these peptide fragments, a subset with the appropriate length and sequence features bind to the groove of MHC class I. Based on the fact that thymoproteasomes have a different peptidase activity from previously discovered constitutive and immunoproteasomes and on analysis results of T cells of various TCR transgenic mice crossed with β5t knockout mice, we have reported the possibility that the thymoproteasome produces special peptides necessary for positive selection. Taken together, we predict that thymoproteasomes produce MHC class I binding peptides in cTEC distinct from other cells, and produce a unique interaction between peptide/MHC class I complex and TCR.
Research3e3.jpgFig. 3 Model of the T cell selection process by the thymoproteasome It is likely that the peptides produced by thymoproteasomes provide the proper interaction for “positive selection” to immature T cells and promote their differentiation into CD8+ T cells.
We aim to elucidate the molecular mechanism of the positive selection process through detailed analysis of peptides presented by MHC class I on cTEC.