Peripheral differentiation patterns of human T cells.

Long-term T-cell memory is dependent on the maintenance of memory T cells in the lymphoid tissues, and at the surface interfaces that provide entry routes for pathogens. However, much of the current information on human T-cell memory is based on analyzing circulating T cells. Here, we have studied the distribution and age-related changes of memory T-cell subsets in samples from blood, mesenteric LNs, spleen, and ileum, obtained from donors ranging in age from 5 days to 67 years of age. Our data show that the main reservoir of polyclonal naive cells is found in the LNs, and the resting memory subsets capable of self-renewal are also prominent there. In contrast, nondividing but functionally active memory subsets dominate the spleen, and especially the ileum. In general, the replacement of naive cells with memory subsets continues throughout our period of observation, with no apparent plateau. In conclusion, the analysis of lymphoid and nonlymphoid tissues reveals a dynamic pattern of changes distinct to each tissue, and with substantial differences between CD4+ and CD8+ compartments.

Critical Drift in a Neuro-Inspired Adaptive Network.

It has been postulated that the brain operates in a self-organized critical state that brings multiple benefits, such as optimal sensitivity to input. Thus far, self-organized criticality has typically been depicted as a one-dimensional process, where one parameter is tuned to a critical value. However, the number of adjustable parameters in the brain is vast, and hence critical states can be expected to occupy a high-dimensional manifold inside a high-dimensional parameter space. Here, we show that adaptation rules inspired by homeostatic plasticity drive a neuro-inspired network to drift on a critical manifold, where the system is poised between inactivity and persistent activity. During the drift, global network parameters continue to change while the system remains at criticality.

Identifying the inheritable component of human thymic T cell repertoire generation in monozygous twins.

We have analyzed T cell receptor repertoires in a unique set of thymus samples from a pair of monozygotic twins. While genetics affect the V(D)J rearrangement and generation of junctional sequences, the thymic selections seem largely stochastic and import no detectable inheritable effect at clonal level.

Generation of self-reactive, shared T-cell receptor α chains in the human thymus.

The T-cell receptor (TCR) repertoire is generated in a semistochastic process of gene recombination and pairing of TCRα to TCRß chains with the estimated total TCR diversity of >108. Despite this high diversity, similar or identical TCR chains are found to recur in immune responses. Here, we analyzed the thymic generation of TCR sequences previously associated with recognition of self- and nonself-antigens, represented by sequences associated with autoimmune diabetes and HIV, respectively. Unexpectedly, in the CD4+ compartment TCRα chains associated with the recognition of self-antigens were generated in significantly higher numbers than TCRα chains associated with the recognition of nonself-antigens. The analysis of the circulating repertoire further showed that these chains are not lost in negative selection nor predominantly converted to the regulatory T-cell lineage. The high abundance of self-reactive TCRα chains in multiple individuals suggests that the human thymus has a predilection to generate self-reactive TCRα chains independently of the HLA-type and that the individual risk of autoimmunity may be modulated by the TCRß repertoire associated with these chains.

Distinguishing subsampled power laws from other heavy-tailed distributions.

Distinguishing power-law distributions from other heavy-tailed distributions is challenging, and this task is often further complicated by subsampling effects. In this work, we evaluate the performance of two commonly used methods for detecting power-law distributions-the maximum likelihood method of Clauset et al. and the extreme value method of Voitalov et al.-in distinguishing subsampled power laws from two other heavy-tailed distributions, the lognormal and the stretched exponential distributions. We focus on a random subsampling method commonly applied in network science and biological sciences. In this subsampling scheme, we are ultimately interested in the frequency distribution of elements with a certain number of constituent parts-for example, species with k individuals or nodes with k connections-and each part is selected to the subsample with an equal probability. We investigate how well the results obtained from low-subsampling-depth subsamples generalize to the original distribution. Our results show that the power-law exponent of the original distribution can be estimated fairly accurately from subsamples, but classifying the distribution correctly is more challenging. The maximum likelihood method falsely rejects the power-law hypothesis for a large fraction of subsamples from power-law distributions. While the extreme value method correctly recognizes subsampled power-law distributions with all tested subsampling depths, its capacity to distinguish power laws from the heavy-tailed alternatives is limited. However, these false positives tend to result not from the subsampling itself but from the estimators' inability to classify the original sample correctly. In fact, we show that the extreme value method can sometimes be expected to perform better on subsamples than on the original samples from the lognormal and the stretched exponential distributions, while the contrary is true for the main tests included in the maximum likelihood method.

Analysis of thymic generation of shared T-cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild-type antigens.

BACKGROUND: The number of mutations in cancer cells is an important predictor of a positive response to cancer immunotherapy. It has been suggested that the neoantigens produced by these mutations are more immunogenic than nonmutated tumor antigens, which are likely to be protected by immunological tolerance. However, the mechanisms of tolerance as regards tumor antigens are incompletely understood. METHODS: Here, we have analyzed the impact of thymic negative selection on shared T-cell receptor (TCR) repertoire associated with the recognition of either mutated or nonmutated tumor antigens by comparing previously known TCR-antigen-pairs to TCR repertoires of 21 immunologically healthy individuals. RESULTS: Our results show that TCRα chains associated with either type of tumor antigens are readily generated in the thymus, at a frequency similar to TCRα chains associated with nonself. In the peripheral repertoire, the relative clone size of nonself-associated chains is higher than that of the tumor antigens, but importantly, there is no difference between TCRα chains associated with mutated or nonmutated tumor antigens. CONCLUSION: This suggests that the tolerance mechanisms protecting nonmutated tumor antigens are non-deletional and therefore potentially reversible. As unmutated antigens are, unlike mutations, shared by a large number of patients, they may offer advantages in designing immunological approaches to cancer treatment.