Naive T cell clonal size is influenced by breadth of self-antigen cross-reactivity

While both B cells and T cells developed to detect foreign antigens, the basic mechanisms behind this process for these two population are fundamentally different. Unlike B cells, T cells recognize foreign epitope presented on MHC plate. The size of epitope detected by T cell receptor (TCR) is usually 9 amino acid long. Such constraint imposed on T cell receptor creates potential for cross-reactivity leading to autoimmunity.

This new study in journal Immunity went further to show that out of 9 amino acids that make up TCR recognition field, changes in only 5 amino acids have the major impact on TCR recognition and T cell population size.

First, the authors, led by Marc Jenkins at the University of Minnesota, Center for Immunology, have determined the population size of mouse naive CD4 T cells specific for a dozen of foreign antigens. Immunization with these specific antigens showed that magnitude of CD4 T cell response correlated with the number of antigen-specific naive T cells.

Next the authors synthesized 11 variant peptides for each 13 peptide examined by substituting each amino acid with alanine at positions P1-P10 ( TCR recognition field). Parental peptide immunized mice were then tested for T cell reactivity to variant peptides in ELISpot assay. The authors found that changes in amino acids in Position 2, 5, 7, 8 could reduce T cell responsiveness by >90%.

To understand how TCR cross-reactivity could affect the variant peptide, 2W109-specific T cell population size and its responsiveness to 2W109, the authors have used act-2W mice that express 2W epitope in the thymus. 2W differs from 2W109 at position 1, 4, 6, 9. Double tetramer staining revealed that compared to B6 mice, in act-2W mice, T cells cross-reactive for both 2W and 2W109 peptide were significantly reduced (B6 mice ~ 180 T cells, act-2W mice ~ 40 T cells). 

Additional experiments indicated that 2W109-specific T cells, that remained in act-2W mice after negative selection, developed heightened sensitivity to amino acid substitution across all 9-mer, including anchor amino acids, implying increased dependency on peptide conformation for TCR recognition.

Indeed, re-analysis of parental foreign peptide-specific T cells responsiveness to variant peptides revealed that increased sensitivity to anchor amino acids substitution correlated with reduction of clonal size, suggesting negative selection against potential self-epitopes.

This study suggests that clonal size of naive T cell specific to any given foreign antigen is determined by the number of self-antigen it happens to cross-react. It addition, these results indicate that TCR cross-reactive for self-epitopes becomes heavily dependent on peptide conformation and may have low affinity for foreign antigens.  

This results, while quite complex, provided a guiding principle how to study T cell responses or how to design T cell specific vaccines.   

Please, leave your comments below. Let me know what do you think about this paper or my analysis.

David Usharauli 

     

What would studying twins could tell us about immune system? Nothing much.

Few weeks ago journal Cell published a study that was widely publicized by online media. The research article came from Mark Davis lab at the Stanford University School of Medicine.

The authors analyzed cellular and serum immune markers in monozygotic (MZ) and dizygotic (DZ) twins to assess the relative contribution of heritable versus non-heritable factors. 

The authors found between 58%-77% of analyzed immune markers are mostly or solely determined by non-heritable, environmental factors. These data suggest that one cannot predict the magnitude and class of the immune response (T_H1,T_H2,...etc) based on inherited gene analyses. In other words, these results would make studying immune-related therapies, like vaccine efficacy or anti-tumor immunology, more complicated and unpredictable.

However, these results were expected, anyway. The point is that immune system and especially the antigen-specific repertoires of adaptive immune system (TCR and BCR) are generated stochastic fashion, even in MZ twins. Unique adaptive immune system affects innate immune system as well. Basically, no humans would have the same immune system, ever. These implies that neither genes nor environment could truly influence or determine the true direction of immune response. It will be random and individualized response. Only immune system and neuronal system have this additional, random, person-specific level of variation.

Interestingly, the authors themselves acknowledge this point in the discussion, however they dismissed it, as not sufficiently significant.

David Usharauli

   

Orphan interferon-lambda vetoes commensal microbes backdoor dealings

This is a second paper in IFN-lambda series. This new paper published in journal Science provided additional confirmation to the earlier study suggesting the role of commensal microbes in norovirus infection. 

The authors showed that antibiotic-treated mice were resistance to chronic intestine norovirus infection.

This resistance to intestine norovirus infection was reversed by normal fecal supplementation implying the role of gut microbes in supporting norovirus infection.

The authors showed that resistance to chronic norovirus infection upon antibiotic treatment were dependent on viral dose and IFN-lambda signaling.

These data suggest that murine norovirus employs endogenous gut microbial flora to establish chronic intestinal infection. It is not clear how microbiota alters IFN-lambda signaling to permit norovirus persistence in the gut.

David Usharauli