A new study showed that there are significant differences in the MHC class II antigens on the insulin peptide that is deficient in type 1 diabetes mellitus (T1DM). These determine the response of the T cells to the insulin peptide that causes destruction of insulin.
The current study found out how peptides are recognized by T cells in the very early part of the autoimmune response. They are now looking at repeating their results in humans, which could help design molecules that can specifically inhibit these T cells. If at-risk patients could be detected in the pre-diabetes phase, the onset of clinical disease could well be prevented.
Researcher Luc Teyton says, “By using single-cell technologies to study the prediabetic phase of disease, we have been able to mechanistically link specific anti-insulin T cells with the autoimmune response seen in type 1 diabetes.”
About 1.25 million people have T1DM just in the USA, which results in acute and severe insulin deficiency. Since insulin clears glucose absorbed from the gut, pushing it into the muscles and other tissues, its deficiency causes high blood sugar levels coupled with the acute lack of fuel for other body tissues. The only way out is to closely monitor their blood sugar levels and use insulin injections to keep it normal.
How T1DM arises
The MHC (major histocompatibility locus) or HLA system is a set of genes that are involved in immune recognition of self and non-self antigens. Genes coding for human leukocyte antigens (HLA) genes were discovered to be linked to autoimmunity over four decades ago. T1DM was linked to mutations in the HLA DR3 and HLA DR4, in particular to the HLA-DQ2 and HLA-DQ8 molecules. This led to the understanding that T cells recognized these mutant molecules on the insulin peptide, leading to T cell attack on insulin. The question remained: how did the T cells get attracted to the HLA molecule?
To answer this, the researchers looked at diabetic mouse blood samples in very early disease, using single-cell analysis and other powerful techniques. This is the first type these T cell types have been tested with such a technique. The result was an incredibly detailed view of how the cell functioned and of genetic differences between various types of T cells.
The P9 switch
Every HLA molecule associated with T1DM has a replacement on the 57th position of the beta chain, where aspartic acid is substituted by a neutral amino acid. This causes an alteration in the surface chemistry which keeps the molecule stable and able to attach to its target peptide. On the other hand, it produces a positively charged patch at a location called the P9 pocket that is exposed to the surface where peptide binding occurs. This skews the MHC II molecule towards binding peptides with acidic amino acids at the right place. However, these diabetogenic MHC II molecules also bind peptides without such a negative charge, leaving the positive patch open for recognition by T cells with more than 30 times the original affinity.
The researchers call this phenomenon the P9 switch. The current study shows that the amino acid at beta-57 position determines which clone of CD4+ cells is activated and expanded for specific insulin peptide binding and destruction.
New MHC molecule to test the P9 switch
This type of T cell recognition could be the basis for autoimmune disorders like celiac disease that are closely linked to such beta-57 aspartic acid-substituted MHC molecules. However, there were no MHC tetramers that could be used to test this hypothesis. The researchers therefore synthesized I-Ag7 tetramers that could bind either of the two types of the Ins9–23 peptide, to test the P9 switch model in T1D.The Ins12–20 peptide has a glycine at P9, while Ins13–21 has a P9 glutamic acid residue.
Normally T cells recognize insulin only after it has been broken down within the antigen presenting cells APCs) into Ins13-21 peptide. However, there is another insulin peptide fragment, Ins12-20, that is not presented by APCs because these cells eliminate it. These are normally presented only when beta cell crinosomes partially break down insulin molecules to fragments and then release them. When the P9 switch is present, T cells are able to recognize these fragments and initiate insulin attack.
If the P9 switch theory is correct, there should be more CD4+ T cells that recognize the peptide-MHC complexes with neutral amino acids at P9. This has been confirmed by earlier studies by the same researchers. Secondly, such T cells should be activated earlier than those which respond to MHC containing either aspartic acid or glutamate residues, because of charge-based interactions.
At the very beginning of the autoimmune response to insulin, the T cells that were mainly seen were the anti-Ins12-20 T cells, which require a P9 switch to recognize the peptide. When aspartic acid was added back at position 57 of the I-Ag7 in vivo, these T cells disappeared.
The study suggests that the P9 switch is more important in initiating an early burst of insulin destruction rather than the progression of T1DM. The P9 switch allows T cell binding to the insulin antigen, facilitating T cell infiltration and autoimmune insulin destruction.
Origin of the anti-insulin T cells
Since every kind of insulin, and its breakdown and mis-synthesis products, is present around the islets, autoimmunity to insulin is most likely to evolve here. The researchers used specific patterns of gene expression to find out where the anti-insulin T cells were produced. Formerly, many thought these might be coming from the pancreatic lymph nodes. However, they found that T cell receptor signaling and T cell expansion occur only in the islet and not in the lymph nodes of the pancreas. Both T helper and T regulatory cells were involved in T cell infiltration of the pancreatic islets.
This study helps understand the role of MHC II molecules in causing autoimmune diabetes. It is possible that small molecule drugs or antibodies that can block the binding capability of the beta-57 position of HLA-DQ8 could prevent the onset of this disease.
The report appeared in the journal Science Immunology on August 30, 2019.
Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset. Louis Gioia, Marie Holt, Anne Costanzo, Siddhartha Sharma, Brian Abe Lisa Kain, Maki Nakayama, Xiaoxiao Wan, Andrew Su, Clayton Mathews, Yi-Guang Chen, Emil Unanue and Luc Teyton. Science Immunology. 30 Aug 2019: Vol. 4, Issue 38, eaaw6329. DOI: 10.1126/sciimmunol.aaw6329. https://immunology.sciencemag.org/content/4/38/eaaw6329
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