Overlapping Peptides Elicit Distinct CD8+ T Cell Responses following Influenza A Virus Infection

Abstract

The presentation of pathogen-derived peptides on MHC class I molecules is essential for the initiation of adaptive CD8+ T cell immunity, which in turn is critical for effective control of many significant human infections. The identification of immunogenic pathogen-derived epitopes and a detailed understanding of how they are recognized by TCRs is essential for the design of effective T cell–based vaccines. In this study, we have characterized the T cell recognition and immune responses in mice to two naturally presented influenza A virus–derived peptides previously identified from virally infected cells via mass spectrometry. These neuraminidase-derived peptides, NA181–190 (SGPDNGAVAV) and NA181–191 (SGPDNGAVAVL), are completely overlapping with the exception of a 1 aa extension at the C terminus of the longer peptide. This minor peptidic difference results in the induction of two completely independent and non–cross-reactive T cell populations that show distinct functional characteristics after influenza A virus infection of B6 mice. We show that the unique TCR reactivity to the overlapping peptides is present in the naive repertoire prior to immune expansion in B6 mice. Moreover, we provide a structural explanation underlying the distinct CD8+ T cell reactivities, which reinforces the concept that peptide length is a key determinant of Ag specificity in CD8+ T cell responses.

Breast cancer is marked by specific, Public T-cell receptor CDR3 regions shared by mice and humans

“…While some literature discusses subsets of this compartment, which include various sub populations, including some that have been referred to as atypical naïve–like memory/effector cells [ 6 ], the vast majority of these cells are naïve. Some recent works show that the unique TCR reactivity to immunogenic pathogen-derived epitopes is present already in the naíve repertoire prior to immune expansion in B6 mice [ 7 ] and that Naïve T cells can manifest shifting to Teffs, which can effectively kill tumor cells [ 8 ]. Interestingly, recent evidence has shown that CD4+ naive T cells significantly more heterogeneous than was previously thought, and that these sub populations of T cells are diverse in phenotypes, differentiation stages, persistence, functions, and anatomic localizations [ 6 ].…”

Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes

“…This might lead to crossrecognition of multiple antigenic peptides, thereby increasing the immunological overlap between self and non-self antigens. The immunological relevance of CD8 + TCRab cross-reactivity is still a matter of debate (60)(61)(62)(63), although seminal studies on potential cross-reactivity of T1D-relevant CD8 + T cell clones for T1D-associated human antigens and pathogens have already been published (28,64,65). In future analyses of cis-spliced epitope candidates, including TCR degeneracy would represent a computational challenge, although it might significantly increase the number of viral-human zwitter epitope candidates potentially associated to T1D.…”

Novel coronavirus mutations: Vaccine development and challenges

“…Current research and development strategies of universal influenza vaccines are designed to protect against a wide range of pathogens [ 154 , 155 ]. Universal influenza vaccine is mainly based on cross-protective T cell response [ 156 , 157 ], and its adjuvants and vaccination methods [ 158 ] have also been studied. All of these strategies could be explored for COVID-19 vaccine development Neutralizing antibodies induced by vaccines are not the only mechanism of protection.…”