One Bug or Another: Promiscuous T Cells Form Lifelong Memory
Authors: Jeffrey C. Nolz, John T. Harty
Journal: Immunity (2013)

As humans age, their T cell repertoire becomes dominated by cells exhibiting “memory” characteristics. In this issue of Immunity, Su et al., 2013Su L.F. Kidd B.A. Han A. Kotzin J.J. Davis M.M. Immunity. 2013; 38 (this issue): 373-383Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar demonstrate that a large percentage of virus-specific CD4+ T cells also exhibit a memory phenotype in unexposed adults. As humans age, their T cell repertoire becomes dominated by cells exhibiting “memory” characteristics. In this issue of Immunity, Su et al., 2013Su L.F. Kidd B.A. Han A. Kotzin J.J. Davis M.M. Immunity. 2013; 38 (this issue): 373-383Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar demonstrate that a large percentage of virus-specific CD4+ T cells also exhibit a memory phenotype in unexposed adults. In the thymus, positive and negative selection results in the generation of CD4+ and CD8+ T cells expressing a diverse repertoire of αβ T cell receptors (TCRs) that recognize foreign, “non-self” peptides presented by major histocompatibility complex (MHC) molecules (Singer et al., 2008Singer A. Adoro S. Park J.H. Nat. Rev. Immunol. 2008; 8: 788-801Crossref PubMed Scopus (333) Google Scholar). Once they are in the periphery, these cells are believed to remain in a “naïve” or quiescent state until they are efficiently activated by antigenic and costimulatory signals. Proper integration of these signaling pathways results in T cell activation that is accompanied by proliferation and the ability to produce cytokines (Jenkins et al., 2001Jenkins M.K. Khoruts A. Ingulli E. Mueller D.L. McSorley S.J. Reinhardt R.L. Itano A. Pape K.A. Annu. Rev. Immunol. 2001; 19: 23-45Crossref PubMed Scopus (387) Google Scholar). After expansion and contraction, the surviving memory T cells are genetically and molecularly different than their naive counterparts, thereby allowing these cells to immediately respond to pathogen reinfection. Although extensive studies using animal models in controlled experimental settings have firmly established this paradigm, far less is known about the characteristics and functions of various antigen-specific T cell populations in humans, in whom environmental factors could have a major impact. Enrichment techniques with peptide-MHC (pMHC) tetramers have recently emerged as a feasible method of studying rare populations of antigen-specific T cells. This approach has resulted in convincing analysis of the preimmune repertoire of antigen-specific CD4+ and CD8+ T cells in laboratory mice (Moon et al., 2007Moon J.J. Chu H.H. Pepper M. McSorley S.J. Jameson S.C. Kedl R.M. Jenkins M.K. Immunity. 2007; 27: 203-213Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar; Obar et al., 2008Obar J.J. Khanna K.M. Lefrançois L. Immunity. 2008; 28: 859-869Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). In this issue of Immunity, Su et al., 2013Su L.F. Kidd B.A. Han A. Kotzin J.J. Davis M.M. Immunity. 2013; 38 (this issue): 373-383Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar used this technique to identify rare populations of antigen-specific CD4+ T cells in humans. As expected, CD4+ T cells specific to various “self-antigens” or common pathogens exhibited a memory-like gene expression profile and produced cytokines after stimulation. However, in unexposed adults (as determined by serological tests), the authors unexpectedly found that a substantial percentage (12%–93% and an average of over 50%) of CD4+ T cells that could bind to MHC-II tetramers loaded with peptides from HIV, cytomegalovirus (CMV), and herpes simplex virus (HSV) also exhibited a memory-like phenotype. In contrast, when the same populations of virus-specific CD4+ T cells were identified in umbilical cord blood samples, a predominantly naive phenotype was observed. These observations suggested that the memory-like characteristics of virus-specific CD4+ T cell populations were not present in the naive immune repertoire found at birth but rather were generated during the time between birth and adulthood. Acquisition of memory-like characteristics of CD8+ T cells without exposure to cognate antigen has been observed in animal models. Overall, these studies concluded that the conversion of T cells from a naive to memory phenotype occurs after homeostatic proliferation driven by cytokines and TCR interactions with self-pMHC (Sprent and Surh, 2011Sprent J. Surh C.D. Nat. Immunol. 2011; 12: 478-484Crossref PubMed Scopus (339) Google Scholar). However, this paradigm is less established for CD4+ T cells, which undergo less homeostatic proliferation than do CD8+ T cells. Because of this, Su et al. considered a second mechanism—that cross-reactivity to environmental antigens could generate memory CD4+ T cells in humans not exposed to the specific pathogen. To test this, the authors used homology searches to identify peptide sequences potentially expressed by other microorganisms and evaluated HIV-specific CD4+ T cell clones for cross-reactivity to the identified peptide sequences. Indeed, approximately 20% of the memory-like HIV-specific CD4+ T cells were stimulated by a peptide sequence found in an unrelated microbe. Thus, TCR cross-reactivity against microbes occurs in the CD4+ T cell repertoire, a finding that has also been described in the human CD8+ T cell compartment (Clute et al., 2005Clute S.C. Watkin L.B. Cornberg M. Naumov Y.N. Sullivan J.L. Luzuriaga K. Welsh R.M. Selin L.K. J. Clin. Invest. 2005; 115: 3602-3612Crossref PubMed Scopus (132) Google Scholar). To determine whether TCR cross-reactivity of human CD4+ T cells could be documented in vivo, Su et al. identified an influenza-specific CD4+ T cell population that would cross-react with peptide sequences that could theoretically be expressed by Finegoldia magna (a commensal bacteria) and Trichomonas vaginalis (a sexually transmitted protozoan). In individuals receiving the 2011 seasonal influenza vaccine A/California/7/2009 (H1N1), this CD4+ T cell population expanded and contracted with kinetics similar to those of other influenza-specific CD4+ T cells. It should be noted, however, that it is unknown whether these peptide sequences identified through a protein database search are naturally processed antigenic targets of F. magna and T. vaginalis or whether exposure to these microbes results in the formation of memory CD4+ T cell populations that will cross-react with influenza antigens. Nevertheless, this demonstrates that CD4+ T cells that can respond to altered peptide ligands found in environmental microorganisms will undergo a proliferative response after influenza vaccination. Overall, the authors suggest that cross-reactivity with antigens found in diverse microorganisms results in the generation of memory-like CD4+ T cells that can respond to specific viruses in individuals without prior exposure to the actual virus (Figure 1 ). Increased overall frequency of antigen-specific CD4+ and CD8+ T cells is a widely accepted characteristic of cellular immune memory (Hammarlund et al., 2003Hammarlund E. Lewis M.W. Hansen S.G. Strelow L.I. Nelson J.A. Sexton G.J. Hanifin J.M. Slifka M.K. Nat. Med. 2003; 9: 1131-1137Crossref PubMed Scopus (673) Google Scholar; Miller et al., 2008Miller J.D. van der Most R.G. Akondy R.S. Glidewell J.T. Albott S. Masopust D. Murali-Krishna K. Mahar P.L. Edupuganti S. Lalor S. et al.Immunity. 2008; 28: 710-722Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar). In contrast, this study found no significant increase in either viral-specific or self-specific CD4+ T cells in unexposed individuals, even though these cells displayed evidence of clonal expansion. By definition, CD4+ T cells reactive against self-antigens should exhibit low-affinity TCR interactions with pMHC-II, given that high-affinity cells should be eliminated in the thymus by negative selection. Low-affinity interactions generally lead to less TCR-mediated proliferation and expansion of T cell populations, suggesting that the memory-like virus-specific CD4+ T cells that develop in unexposed humans might also be the result of low-affinity TCR interactions. However, it remains to be determined whether TCR cross-reactivity to environmental microbes, rather than the previously defined development of memory-like T cells through homeostatic proliferation, is the causative mechanism for cross-reactive CD4+ T cell memory (Sprent and Surh, 2011Sprent J. Surh C.D. Nat. Immunol. 2011; 12: 478-484Crossref PubMed Scopus (339) Google Scholar). Finally, one question that remains is whether the generation of these memory-like CD4+ T cell populations is beneficial (or potentially detrimental) with regard to human health. Su et al. speculate that the generation of cross-reactive memory-like CD4+ T cell populations might broaden the range of pathogens that can be efficiently recognized by the immune system. In contrast, it is also possible that cross-reactive CD4+ T cell populations could contribute to autoimmune disorders, in which exposure to common microbes could lead to the generation of CD4+ T cells that recognize self-antigens (Sewell, 2012Sewell A.K. Nat. Rev. Immunol. 2012; 12: 669-677Crossref PubMed Scopus (292) Google Scholar). Careful prevaccination and postvaccination analysis of cross-reactive antigen-specific T cell populations in large cohorts of subjects and subsequent extensive longitudinal analysis of disease prevalence will be required for furthering our understanding of the physiological relevance of these cell populations in humans. Virus-Specific CD4+ Memory-Phenotype T Cells Are Abundant in Unexposed AdultsSu et al.ImmunityFebruary 7, 2013In BriefAlthough T cell memory is generally thought to require direct antigen exposure, we found an abundance of memory-phenotype cells (20%–90%, averaging over 50%) of CD4+ T cells specific to viral antigens in adults who had never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. In contrast, the same T cell receptor (TCR) specificities in newborns are almost entirely naïve, which might explain the vulnerability of young children to infections. Full-Text PDF Open Archive