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Title: A Genetic and Functional Relationship between T Cells and Cellular Proliferation in the Adult Hippocampus}
Article:
Abstract:
Neurogenesis continues through the adult life of mice in the subgranular zone of the dentate gyrus in the hippocampus, but its function remains unclear. Measuring cellular proliferation in the hippocampus of 719 outbred heterogeneous stock mice revealed a highly significant correlation with the proportions of CD8+ versus CD4+ T lymphocyte subsets. This correlation reflected shared genetic loci, with the exception of the H-2Ea locus that had a dominant influence on T cell subsets but no impact on neurogenesis. Analysis of knockouts and repopulation of TCRα-deficient mice by subsets of T cells confirmed the influence of T cells on adult neurogenesis, indicating that CD4+ T cells or subpopulations thereof mediate the effect. Our results reveal an organismal impact, broader than hitherto suspected, of the natural genetic variation that controls T cell development and homeostasis.
Introduction:
The discovery that neurogenesis occurs in the adult hippocampus has attracted considerable attention, yet its function remains unclear[1],[2]. Adult neurogenesis is known to occur in two areas of the mammalian brain, the subventricular zone, which gives rise to olfactory bulb interneurons, and the dentate gyrus of the hippocampal formation, which gives rise to granule cells[3]. Its occurrence in the latter structure has prompted considerable speculation that it is involved in known functions of the hippocampus: learning, memory, and emotional regulation. However, the hippocampal function of adult neurogenesis is still debated. Experiments using antimitotic agents and irradiation to kill newly dividing cells in the brain have produced conflicting results( reviewed in[4]). Genetically targeted ablation of neurogenesis also reports contrasting effects: normal learning and memory[5], normal anxiety with a reduction in contextual freezing and normal spatial memory[6], no change in freezing but impaired spatial memory[7],[8], a combined impairment of spatial memory and reduction of contextual freezing responses[9],[10], or increased anxiety but no effect on spatial memory[11]. While it is possible that the behavioural effects of neurogenesis ablation are subtle( a recent report argues that they include specific impairments in spatial discrimination[1]), it may also be the case that adult neurogenesis has additional roles. Here we adopted a genetic approach to address this question. Rates of adult hippocampal neurogenesis differ between inbred strains of mice, indicating that quantitative trait loci( QTL) contribute to this variation[12]. We asked if QTLs influencing neurogenesis could be found that influenced other phenotypes, which might cast light on the function of neurogenesis. We decided to map variation in adult hippocampal neurogenesis in heterogeneous stock( HS) mice, a stock descended from eight inbred progenitor strains( A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, and LP/J) and maintained for over 50 generations[13]. The large number of recombinants that have accumulated since the founding of the stock means that QTLs are mapped to an average region of 3 Mb, so that co-localization is more likely to reflect pleiotropic action than co-incident location. The HS is unique not only for its high resolution and the number of QTLs that have been mapped( 843)[13] but also for the diversity of traits analysed, including disease models( asthma, anxiety, and type 2 diabetes), as well as haematological, immunological, biochemical, and anatomical assays. The phenotypes include those previously suggested to be related to neurogenesis: novelty suppressed feeding[14], measures of anxiety taken in an elevated plus maze and open field, and contextual fear conditioning( data are freely available from http://gscan. well. ox. ac. uk)[9]–[11]. Our aim was to explore the relationship of these, and other, phenotypes to adult neurogenesis in the HS mice.
Discussion:
Our analysis of a large stock of outbred mice makes two novel observations about adult neurogenesis in the hippocampus. First, we find a correlation between variation in cellular proliferation in the hippocampus and the relative proportions of CD4+ and CD8+ subsets of αβT cells. The correlation is much larger than that found for over 90 other phenotypes. Second, the correlation is driven by genetics: QTLs that contribute to variation in cell proliferation in the hippocampus also contribute to variation in the relative proportions of CD4+ and CD8+ T cells. Importantly, the genetic correlation is due to natural sequence variants that differentiate inbred strains of laboratory mice. Our findings extend previous observations that T cells contribute to variation in adult neurogenesis[22],[23]. Previously, analysis of mice with a mutation that ablated both T- and B-lymphocyte compartments showed impairment of adult neurogenesis, which could be restored by repopulation with mono-specific T cells recognizing a CNS-antigen( myelin basic-protein). This was interpreted as an effect of autoimmune attack[22]. Reduced adult neurogenesis was also found in mice with no T or B cells due to a mutation in either RAG1 or RAG2[23]. Repopulation and depletion experiments again implicated T cells[23]. The latter experiments, together with analysis of CD4−/− mice, indicated that CD4+ T cells contributed to adult neurogenesis, regardless of their antigen specificity. Results obtained from the HS indicate that the relationship between T cells and cellular proliferation in the hippocampus is not merely an artefact of transgenic or knockout mice, or of the very unusual conditions created in alymphoid mice upon immune reconstitution, but arises from the far more subtle cues of natural genetic variation: loci that contribute to variation in cell proliferation in the hippocampus also contribute to variation in the relative proportions of CD4+ and CD8+ T cells. Naturally occurring genetic variation is a very different setting( and obviously more physiogically relevant) than the gross abnormalities of knockout mice. Two questions follow: why do T cells influence neurogenesis in the hippocampus, and how do they do it? Our data suggest a broader role for T cell function on adult neurogenesis than previously suspected[22],[23]. The strikingly large correlation between cellular proliferation in the hippocampus and T cell subsets, attributable to naturally occurring genetic variation, suggests that the correlation itself is functionally important( otherwise it would have decayed through stochastic fluctuation in allele frequencies). The strong correlation contrasts with the weak, often non-significant, correlation with behavioural phenotypes often invoked as functional consequences of adult neurogenesis. This suggests that modulation of the behavioural functions of the hippocampus may not be the primary role of neurogenesis. Postulated roles in learning and memory may in fact be secondary to the immunological[1],[2]. For example, anything that alters the ratio of CD4+ to CD8+ cells might alter behaviour, so that variation in behavioural results from different laboratories[1],[2] could be due to differences in the health status of the animals. It is also interesting to note alterations in CD4+ lymphocytes may affect human behaviour. For example, the mechanism by which human immunodeficiency virus type 1( HIV-1) produces dementia remains obscure[24]. Impairment of neurogenesis is suspected to play a part[25],[26] and this may be mediated in part by reduction in CD4+ lymphocytes. How do T cells influence neurogenesis in the hippocampus? This is difficult to explain, given that T cells are very rare in the brain under normal circumstances. Moreover genetic mapping experiments, and those performed in knockout or reconstituted mice, appear to give different clues about mechanism: analysis of the HS mice pointed to the involvement of CD8+ T cells, as their frequency correlated with increased neurogenesis, while the analysis of knockouts and repopulation experiments implicated CD4+ T cells, here and in the work of Wolf et al.[23]. An important clue comes from the delineation of the QTLs that affect both T cell and neurogenesis phenotypes. All QTLs that control the proportions of CD4+ and CD8+ T cells also have an impact on neurogenesis, with the glaring exception of the strongest of them, the H2-Ea locus[17], whose homolog has also been identified in human GWAS studies of CD4+/CD8+ ratio determinism[18]. H2-Ea allows the assembly of a functional EαEβ MHC-II heterodimer. In turn, this E heterodimer, by presenting an array of self-peptides, can select and support a large population of “E-restricted” CD4+ T cells. H2-Ea is frequently inactivated by deletions or other mutations that are widespread among inbred and wild mice[27],[28], and such mice( including the C57BL/6 founder of the HS stock) only have the AαAβ MHC-II complex and A-restricted CD4+ T cells. E-restricted CD4+ T cells are functionally effective by all measures tested[29], but the strong protective effect of H-2Ea against autoimmune diseases such as Type-1 diabetes suggests that E- and A-restricted repertoires are not always equivalent. In the present context, the absence of a neurogenesis QTL mapping to H-2Ea suggests that the connection between CD4+ T cells and neurogenesis is a property that can be uniquely fulfilled by A-restricted cells, implying a role for specific TCR/MHC interactions, rather than a generic effect of the relative proportions of CD4+ and CD8+ T cells. In regards to the apparent discrepancy between the impact of natural genetic variation and the results of experimental manipulation, it is important to realize that different populations are being affected in the different modalities. CD4+ T cells are a complex mix of cells. Some of them have positive effector functions, while others exhibit regulatory potential over other cells of the immune system and also over non-lymphoid organs such as the adipose tissue( in particular FoxP3+ “Treg” cells[30],[31]). While natural variation might equally affect all CD4+ T cells, the conditions created by the lineage deficiency of MHC knockouts, which still have a significant Treg component, or by the homeostasis-driven proliferation that occurs after reconstitution of lymphopenic hosts[32] may result in an altered balance of effector versus regulatory T cells. Thus, the same subpopulations of CD4+ T cells are not equally affected in all instances, and a unifying interpretation may be that neurogenesis positively correlates with the relative proportion of CD4+ and CD8+ effector relative to Treg cells. In cellular terms, how A-restricted effector or regulatory T-cells influence hippocampal activity remains conjectural. One might hypothesize direct interactions occurring in the hippocampus between CD4+ T cells and MHC-II+ microglia. CD4+ T cells are very rare but not completely absent in this anatomical location. Alternatively, the hippocampus may be responding to long-range mediators released by T cells, for instance the cytokines released during T cell activation in lymphoid organs. One candidate for the molecular mechanism set in motion by T cells is the Wnt pathway[33],[34]. Wnt signalling components are expressed in adult hippocampal progenitor cells and modulate the generation of newborn neurons[35]. Inhibition of Wnt signalling increases the number of new neurons and leads to a loss of stem cell multipotency[36]. Manipulation of recently identified components of the Wnt pathway( NEUROD1[37],[38] and DISC1[39]) also alters the production of new neurons. However, mediators between T cells and the Wnt pathway are unknown. We expect clues to their identity to emerge from identifying the molecules under the QTLs that co-regulate T cells and cellular proliferation in the hippocampus. Mapping resolution in the HS is approximately 3 Mb, insufficient to formally identify single genes. However, it is worth noting that the locus on chromosome 6 contains the Cd8a and Cd8b genes, whose products are expressed in CD4+CD8+ immature precursors in the thymus, and would be expected to influence lineage commitment to either the CD4+ or CD8+ lineages. A locus on chromosome 13 contains Fst( Follistatin), already known to be involved in adult neurogenesis[40]. The interaction between neurogenesis and T cell subsets is another example of neural-immune communication across the blood brain barrier: it is now clear that this happens outside of disease states[41] and that a common molecular machinery may operate in neurons and immune cells. Major histocompatibility molecules and parts of the complement cascade are involved in neural development and function[42]; many of the same cell adhesion molecules regulate the specificity of interactions at both neuronal and immunological synapses[43]. Our insights into the role of T cells in adult neurogenesis depended upon access to multiple phenotypes obtained in a set of genotyped animals. The delineation of biological control pathways is hard to achieve through experiments that test one phenotype, and one gene, at a time. The approach used here is likely to become more common with the availability of genetic reference populations, such as the collaborative cross[44],[45].
In adult mice new neurons are produced in the hippocampus , where they are thought to influence learning , memory , and emotional regulation . The mechanisms and functions of this neurogenesis , however , remain unclear . Here we report that in different strains of mice , variation in cellular proliferation in the hippocampus ( an index of neurogenesis ) correlates with variation in the relative proportions of the ratio of CD4+ to CD8+ T cells ( an immunology phenotype ) . We also show that T cells can influence neurogenesis ( but that neurogenesis does not influence T cells ) by analyzing knockouts , depleting mice of T cells , and repopulating alymphoid animals . The strong genetic correlation between T cells and cellular proliferation in the hippocampus contrasts with the weak , often non-significant , correlation with behavioral phenotypes . Of significance , the findings here suggest that modulation of the functions of the hippocampus to influence behavior is not the primary role of neurogenesis .