Overtly self-reactive T cells are removed during thymic selection. However, it has been recently established that T cell self-reactivity promotes protective immune responses. Apparently, the level of ...self-reactivity of mature T cells must be tightly balanced. Our mathematical model and experimental data show that the dynamic regulation of CD4- and CD8-LCK coupling establish the self-reactivity of the peripheral T cell pool. The stoichiometry of the interaction between CD8 and LCK, but not between CD4 and LCK, substantially increases upon T cell maturation. As a result, peripheral CD8+ T cells are more self-reactive than CD4+ T cells. The different levels of self-reactivity of mature CD8+ and CD4+ T cells likely reflect the unique roles of these subsets in immunity. These results indicate that the evolutionary selection pressure tuned the CD4-LCK and CD8-LCK stoichiometries, as they represent the unique parts of the proximal T cell receptor (TCR) signaling pathway, which differ between CD4+ and CD8+ T cells.
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•Coupling of CD8-LCK but not CD4-LCK increases upon T cell maturation•Dynamics of coreceptor-LCK coupling stoichiometry establish T cell self-reactivity•CD8+ T cells are more self-reactive than CD4+ T cells
Horkova et al. reveal dynamic regulation of the coreceptor-LCK interaction during T cell development, establishing the self-reactivity of mature T cells. Differences between CD8 and CD4 coreceptors cause peripheral CD8+ T cells to be more self-reactive than CD4+ T cells.
The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active ...conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.
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•LFA-1 mediated co-stimulation of CD8+ T cells depends on extracellular magnesium•Magnesium is sensed via LFA-1 and regulates the effector function of CD8+ T cells•Low serum magnesium levels are associated with worse outcomes in cancer immunotherapy•The magnesium-LFA-1 axis has translational potential
The T cell co-stimulatory molecule LFA-1 binds extracellular magnesium ions, allowing it to modulate murine and human CD8+ T cell effector function in response to magnesium levels during normal responses and in the context of immunotherapy.
Significance T-cell receptor recognition of antigen is an essential first step in the initiation of a T-cell response. This report demonstrates that CD4 T cells responding during an infection can ...discriminate between antigen affinity and antigen dose, resulting in distinct types of effector and memory cell generation. Moreover, memory T cells “remember” the strength of primary T-cell activation and maintain a biased recall response upon secondary infection. These data reveal that antigen affinity exerts an important influence on T-cell differentiation that is not compensated for by high antigen dose. Understanding the rules of CD4 T-cell differentiation is integral to effective vaccine design.
Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen. In contrast, follicular helper T cell (T FH) effectors are generated after priming with high, intermediate, and low affinity ligand. Unexpectedly, memory T cells generated after priming with very low affinity antigen remain impaired in their ability to generate secondary Th1 effectors, despite being recalled with high affinity antigen. These data challenge the view that only strongly stimulated CD4 T cells are capable of differentiating into the T FH and memory T-cell compartments and reveal that differential strength of stimulation during primary T-cell activation imprints unique and long lasting T-cell differentiation programs.
T resident memory (Trm) cells provide a first line of defense in non-lymphoid tissues. A new report in Nature Immunology by Fonseca et al. reveals that CD8+ Trm cells can give rise to circulating ...effector and memory T cells, but remain predisposed to migrate back into their tissue of origin.
The present genetic diversity of commensal rodent populations is often used to inform the invasion histories of these species, and as a proxy for historical events relating to the movement of people ...and goods. These studies assume that modern genetic diversity generally reflects early colonising events. We investigate this idea by sequencing the mitochondrial DNA of rodent bones found in a 19th-century archaeological site in The Rocks area of Sydney, Australia, the location of the first historical European port (Port Jackson) in Australasia. We also interpret the history of rodent invasions in New Zealand based on this evidence, as Sydney was the primary port from which European boats sailed to New Zealand. We identified 19th-century bones from two species, Norway rats (
Rattus norvegicus
) and house mice (
Mus musculus domesticus
). We found six historical genetic haplotypes in the 39 Norway rats, showing either multiple early introductions or a diverse initial founding population. One of them was identical with Norhap01 common in the North Island of New Zealand, but none was like the haplotype Norhap02 found throughout the South Island. We found three haplotypes in seven house mice, all belonging to the dominant subspecies established in Australia,
M.m. domesticus
. We had few modern Norway rat and house mouse DNA sequences from Sydney, but those we had did tentatively support the hypotheses that (1) modern samples can represent at least a preliminary estimate of historical diversities and origins, and (2) Asian haplotypes of both Norway rats and of house mice reached the South Island of New Zealand early in colonial times direct from China rather than through Port Jackson.
A hallmark of adaptive immunity is CD4 T cells' ability to differentiate into specialized effectors. A long-standing question is whether T cell receptor (TCR) signal strength can dominantly instruct ...the development of Th1 and T follicular helper (Tfh) cells across distinct infectious contexts. We characterized the differentiation of murine CD4 TCR transgenic T cells responding to altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that TCR signal strength exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells responding to acute versus persistent infection. TCR signal strength correlates positively with Th1 generation during acute but negatively during chronic infection. Weakly activated T cells express lower levels of markers associated with chronic T cell stimulation and may resist functional inactivation. We anticipate that the panel of recombinant viruses described herein will be valuable for investigating a wide range of CD4 T cell responses.
Autism is hypothesized to represent a disorder of brain connectivity, yet patterns of atypical functional connectivity show marked heterogeneity across individuals.
We used a large multi-site dataset ...comprised of a heterogeneous population of individuals with autism and typically developing individuals to compare a number of resting-state functional connectivity features of autism. These features were also tested in a single site sample that utilized a high-temporal resolution, long-duration resting-state acquisition technique.
No one method of analysis provided reproducible results across research sites, combined samples, and the high-resolution dataset. Distinct categories of functional connectivity features that differed in autism such as homotopic, default network, salience network, long-range connections, and corticostriatal connectivity, did not align with differences in clinical and behavioral traits in individuals with autism. One method, lag-based functional connectivity, was not correlated to other methods in describing patterns of resting-state functional connectivity and their relationship to autism traits.
Overall, functional connectivity features predictive of autism demonstrated limited generalizability across sites, with consistent results only for large samples. Different types of functional connectivity features do not consistently predict different symptoms of autism. Rather, specific features that predict autism symptoms are distributed across feature types.
Influenza is a deadly and costly infectious disease, even during flu seasons when an effective vaccine has been developed. To improve vaccines against respiratory viruses, a better understanding of ...the immune response at the site of infection is crucial. After influenza infection, clonally expanded T cells take up permanent residence in the lung, poised to rapidly respond to subsequent infection. Here, we characterized the dynamics and transcriptional regulation of lung-resident CD4
T cells during influenza infection and identified a long-lived,
dependent population that we have termed T resident helper (T
) cells. T
cells arise in the lung independently of lymph node T follicular helper cells but are dependent on B cells, with which they tightly colocalize in inducible bronchus-associated lymphoid tissue (iBALT). Deletion of
in CD4
T cells before heterotypic challenge infection resulted in redistribution of CD4
T cells outside of iBALT areas and impaired local antibody production. These results highlight iBALT as a homeostatic niche for T
cells and advocate for vaccination strategies that induce T
cells in the lung.
The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and ...distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) Treg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) Tconv cells into induced Treg cells (iTreg cells). Although Foxp3-deficient (Scurfy) mice lacked Treg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells zsuper> T cells infiltrated the skin, whereas Scurfy Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of Treg cells into distinct subsets with non-overlapping regulatory activities.
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