Deviations in influenza seasonality: odd coincidence or obscure consequence?

In temperate regions, influenza typically arrives with the onset of colder weather. Seasonal waves travel over large spaces covering many climatic zones in a relatively short period of time. The precise mechanism for this striking seasonal pattern is still not well understood, and the interplay of factors that influence the spread of infection and the emergence of new strains is largely unknown. The study of influenza seasonality has been fraught with problems. One of these is the ever-shifting description of illness resulting from influenza and the use of both the historical definitions and new definitions based on actual isolation of the virus. The compilation of records describing influenza oscillations on a local and global scale is massive, but the value of these data is a function of the definitions used. In this review, we argue that observations of both seasonality and deviation from the expected pattern stem from the nature of this disease. Heterogeneity in seasonal patterns may arise from differences in the behaviour of specific strains, the emergence of a novel strain, or cross-protection from previously observed strains. Most likely, the seasonal patterns emerge from interactions of individual factors behaving as coupled resonators. We emphasize that both seasonality and deviations from it may merely be reflections of our inability to disentangle signal from noise, because of ambiguity in measurement and/or terminology. We conclude the review with suggestions for new promising and realistic directions with tangible consequences for the modelling of complex influenza dynamics in order to effectively control infection.

The privacy of T cell memory to viruses.

T cell responses to viral infections can mediate either protective immunity or damaging immunopathology. Viral infections induce the proliferation of T cells specific for viral antigens and cause a loss in the number of T cells with other specificities. In immunologically naive hosts, viruses will induce T cell responses that, dependent on the MHC, recognize a distinct hierarchy of virus-encoded T cell epitopes. This hierarchy can change if the host has previously encountered another pathogen that elicited a memory pool ofT cells specific to a cross-reactive epitope. This heterologous immunity can deviate the normal immune response and result in either beneficial or harmful effects on the host. Each host has a unique T cell repertoire caused by the random DNA rearrangement that created it, so the specific T cells that create the epitope hierarchy differ between individuals. This "private specificity" seems of little significance in the T cell response of a naive host to infection, but it is of profound importance under conditions of heterologous immunity, where a small subset of a cross-reactive memory pool may expand and dominate a response. Examples are given of how the private specificities of immune responses under conditions of heterologous immunity influence the pathogenesis of murine and human viral infections.

Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets.

CD1d-restricted invariant NKT (iNKT) cells are immunoregulatory cells whose loss exacerbates diabetes in nonobese diabetic (NOD) female mice. Here, we show that the relative numbers of iNKT cells from the pancreatic islets of NOD mice decrease at the time of conversion from peri-insulitis to invasive insulitis and diabetes. Conversely, NOD male mice who have a low incidence of diabetes showed an increased frequency of iNKT cells. Moreover, administration of alpha-galactosylceramide, a potent activating ligand presented by CD1d, ameliorated the development of diabetes in NOD female mice and resulted in the accumulation of iNKT cells and myeloid dendritic cells (DC) in pancreatic lymph nodes (PLN), but not in inguinal lymph nodes. Strikingly, injection of NOD female mice with myeloid DC isolated from the PLN, but not those from the inguinal lymph nodes, completely prevented diabetes. Thus, the immunoregulatory role of iNKT cells is manifested by the recruitment of tolerogenic myeloid DC to the PLN and the inhibition of ongoing autoimmune inflammation.

Regulation of CD1 function and NK1.1(+) T cell selection and maturation by cathepsin S.

NK1.1(+) T cells develop and function through interactions with cell surface CD1 complexes. In I-A(b) mice lacking the invariant chain (Ii) processing enzyme, cathepsin S, NK1.1(+) T cell selection and function are impaired. In vitro, thymic dendritic cells (DCs) from cathepsin S(-/-) mice exhibit defective presentation of the CD1-restricted antigen, alpha-galactosylceramide (alpha-GalCer). CD1 dysfunction is secondary to defective trafficking of CD1, which colocalizes with Ii fragments and accumulates within endocytic compartments of cathepsin S(-/-) DCs. I-A(k), cathepsin S(-/-) mice do not accumulate class II-associated Ii fragments and accordingly do not display CD1 abnormalities. Thus, function of CD1 is critically linked to processing of Ii, revealing MHC class II haplotype and cathepsin S activity as regulators of NK T cells.

A class I MHC-restricted recall response to a viral peptide is highly polyclonal despite stringent CDR3 selection: implications for establishing memory T cell repertoires in "real-world" conditions.

In this study, we analyze the recall response to influenza A matrix peptide M1(58-66) restricted by HLA-A2 in one individual and find a strict CDR3 selection as well as a high degree of polyclonality. The TCR beta-chain repertoire of memory T cells specific for this Ag system has been shown previously to be constrained by the use of the BV17 family and the I/sRS(A)/S amino acid motif in the CDR3 region. Our sequence analysis of BV17 TCR from a CTL line showed the repertoire to be highly polyclonal, as 95 distinct CDR3 sequences (clonotypes) were identified expressing this CDR3 motif. The clonotype frequencies showed a power law distribution with an extensive low-frequency tail. The clonotypes present in the high-frequency component of the distribution could be measured directly in the PBMC. This measurement showed that the relative frequencies of these clonotypes before stimulation were similar to their frequencies after culturing. Analysis of short-term cultures showed that the responding clonotypes have a similar ability to proliferate, which is independent of TCR beta-chain CDR3 sequence or precursor frequency. These data indicate that the memory T cell repertoire is composed of a surprisingly diverse set of T cell clonotypes with a limited potential for expansion. We propose that the high-frequency component represents T cells that have existed the longest. In keeping with this hypothesis, these clonotypes were measured over a 2-year period, during which their precursor frequency did not change.

CD4+ and CD8+ circulating alpha/beta T-cell repertoires are equally complex and are characterized by different levels of steady-state TCR expression.

The repertoire complexity of CD4+ and CD8+ T cells was measured in three healthy blood donors for a number of TCR BV gene families by TCR spectratyping. This method subdivides V family-specific PCR products based on CDR3 length. Genomic DNA was analyzed to determine the distribution of the cells bearing particular V-J rearrangements. cDNA was analyzed to measure the levels of transcripts arising from those same cells. The complexity and distribution of T cells in each lineage were equal for most BV families. Certain families showed frequent skewing in CD8 cells. Analysis of the intensity profiles of RNA versus DNA spectratypes indicated that in general, there is a constant ratio of transcript per cell for all rearranged sizes within a particular family. This ratio appeared higher in CD4 cells. Thus, steady state levels of TCR mRNA were measured and found to be higher in CD4+ than in CD8+ cells.

Search for MHC-associated genes in human: five new genes centromeric to HLA-DP with yet unknown functions.

Taking advantage of five mouse genomic or cDNA probes [KE5(probe 14), KE4 (probe 11), KE3 (probe 7), KE2 (probe 5), and SET] mapped on the H-2K region in mouse, we have identified and localized homologues of these five genes in the human major histocompatibility complex region (HKE5, HKE4, HKE3, HKE2, and HSET, respectively). Cosmid cloning and pulsed field gel electrophoresis analyses indicated that a human homologous gene, HKE5, is located 10 kilobases (kb) centromeric of the alpha 2 (XI) collagen (COL11A2) gene followed by HKE4. HKE3, closely linked to HKE2, is located 170 kb centromeric of HKE4. Furthermore, HSET is located 50 kb centromeric of HKE2. This gene organization outside the DP subregion is completely identical to that of the mouse H-2K region centromeric of I-Pb3, a mouse homologue of the DPB gene, except the lack of genes corresponding to the H-2K and -K2 genes in human.