Development of Anti-viral CD4+ T cells in unexposed individuals

HIVIn a study published in the February 2013 issue of Immunity, Su. et. al., characterized the CD4+ T cell repertoire from adult human peripheral blood mononuclear cells (PBMC) and made a fascinating observation: that memory T cells can develop against pathogens the host has never been exposed to, including HIV-1, cytomegalovirus (CMV), and herpes simplex virus (HSV).

To determine the baseline frequencies of pathogen and self-antigen-specific CD4+ T cell populations in naive individuals by flow cytometry, PBMCs were stained with major histocompatibility complex (MHC)-peptide tetramers for HLA-DR4 -restricted epitopes.  The MHC-peptides assessed included peptides from viral pathogens including HIV-1 (gag p24), CMV (pp65), and HSV (VP16), as well as self-peptides: the melanoma-associated antigen gp100, the arthritis-associated antigen fibrinogen, and the diabetes-associated antigen preproinsulin. For both self and pathogen-associated antigens, the frequency of tetramer-positive cells was found to be one to ten cells per million CD4+ T cells, in individuals previously unexposed to these viruses.  Prior exposure to viral pathogens was determined by highly sensitive serological tests.

Interestingly, on average across individuals, greater than 50% of these antigen-specific CD4+ T cells were found to be memory T cells based on CD45RO+ staining and expression of CD4+ memory T cell-associated genes.  Furthermore, viral antigen-specific CD45RO+ memory T cells secreted IFNg when stimulated with phorbol myristate acetate (PMA) plus ionomycin.  Sequencing of the TCR-beta chain from naïve and memory HIV-1-specific CD4+ T cells indicated that the antigen-specific memory phenotype but not naive CD4+ T cell populations had arisen from clonal expansion.  Thus the memory phenotype of these antigen-specific T cells indicates prior antigen experience and subsequent clonal expansion.

The question remained though, as to how individuals had developed CD4+ memory T cell responses against pathogens they had not apparently been exposed to.  One hypothesis for the existence of these CD4+ memory T cell populations is development via cross-reactivity to other antigens.  BLAST analysis of the HIV-1 peptide sequence identified several similar sequences present in gut and soil-resident bacteria, marine algae, and plants.  HIV-1-specific CD4+ memory T cell clones from various individuals showed cross-reactivity to several of these environmental microbial antigens as measured by production of IFNg and IL-2, and proliferation when stimulated with MHC-peptides.  Interestingly, antigen-specific CD4+ memory T cells elicited by vaccination of individuals with an H1N1 influenza virus vaccine were reciprocally cross reactive to several other microorganisms.

Overall, this study shows that pathogen-specific CD4+ memory T cells commonly arise in individuals through exposure to other environmental microbes containing similar peptide sequences.  The question remains however, as to whether these cross-reactive antigen-specific T cells are able to exhibit protective immune responses.


Further Reading:

Virus-Specific CD4 (+) Memory-Phenotype T Cells Are Abundant in Unexposed Adults.  Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM. Immunity. 2013 Feb 5. pii: S1074-7613(13)00052-6.

Derivation and maintenance of virtual memory CD8 T cells.  A.D. Akue, J.Y. Lee, S.C. Jameson.  J. Immunol., 188 (2012), pp. 2516 – 2523

Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. B.D. Rudd, V. Venturi, G. Li, P. Samadder, J.M. Ertelt, S.S. Way, M.P. Davenport, J. Nikolich-Žugich.  Proc. Natl. Acad. Sci. USA, 108 (2011), pp. 13694–13699.

Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans.  I. den Braber, T. Mugwagwa, N. Vrisekoop, L. Westera, R. Mögling, A.B. de Boer, N. Willems, E.H. Schrijver, G. Spierenburg, K. Gaiser et al.  Immunity, 36 (2012), pp. 288–297

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