Terekhova et al. assemble a single-cell PBMC atlas of 8 datasets, 2,609 individuals, and over 12 million cells to dissect variable and conserved features of human immune aging. CD8+ Tem GZMK+ to GZMB+ ratio distinguishes healthy from disease-associated trajectories and predicts mortality risk. This work provides a clinically relevant marker for monitoring human aging.

Read the full paper: Single-cell analyses of global cohorts outline determinants of immune aging and link the ratio of GZMK+ to GZMB+ Tem cells to health trajectories

Malaria, a pervasive and devastating disease, is characterized by systemic complications and dysregulated host immune responses to Plasmodium infectio…

Source: GEN (Genetic Eng News)

A Landmark Study of Our Immune System Aging With A Promising Blood Test

Here we analyzed the relative contributions of CD4+ regulatory T cells expressing Forkhead box protein P3 (FOXP3) and CD8+ regulatory T cells expressing killer cell immunoglobulin-like receptors to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB respectively encode proteins FOXP3 and granzyme B, which are critical to the suppressive functions of CD4+ and CD8+ regulatory T cells. Using CRISPR–Cas9 gene editing, we were able to achieve a reduction of ~90–95% in the expression of these genes. FOXP3 knockout in tonsil T cells led to production of antibodies against a variety of autoantigens and increased the affinity of influenza-specific antibodies. By contrast, GZMB knockout resulted in an increase in follicular helper T cells, consistent with the ablation of CD8+ regulatory T cells observed in mouse models, and a marked expansion of autoreactive CD8+ and CD4+ T cells. These findings highlight the distinct yet complementary roles o

Read the full paper: Ferroptosis-STING co-activation drives GzmB+CD38+CD8+ T-cell expansion to overcome lymphoma immunosuppression

Cytotoxicity-associated genes exhibit heterogeneity at the cellular and tissue levels (left). NKG7 gene expression is strongly associated with a cytotoxic gene signature (middle). NKG7 expression is ...

γδIELs are essential for intestinal homeostasis, but how their differentiation and cytotoxic function are regulated remains unclear. Xie et al. demonstrate two functionally distinct γδIEL subsets, CD160+TCF1+BCL6+ stem-like and GZMB+BLIMP1+ effector-like cells, and show that Salmonella infection promotes IL-12/TCR-STAT4-BLIMP1 signaling to drive effector differentiation and cytotoxicity, linking γδIEL responses to microbial-derived cues for protective gut immunity.

γδIELs are essential for intestinal homeostasis, but how their differentiation and cytotoxic function are regulated remains unclear. Xie et al. demonstrate two functionally distinct γδIEL subsets, CD160+TCF1+BCL6+ stem-like and GZMB+BLIMP1+ effector-like cells, and show that Salmonella infection promotes IL-12/TCR-STAT4-BLIMP1 signaling to drive effector differentiation and cytotoxicity, linking γδIEL responses to microbial-derived cues for protective gut immunity.

CD8+ T cells, traditionally recognized for their cytotoxic role in eliminating infections and malignancies, are now known to exhibit significant functional heterogeneity, as revealed by single-cell genomics. Among these, granzyme-K-expressing (GZMK+) CD8+ T cells represent a distinct subset characterized by low cytotoxicity but heightened proinflammatory activity, by contrast with their granzyme-B-expressing (GZMB+) counterparts with high cytotoxicity. GZMK+CD8+ T cells are often more abundant in inflammatory diseases, cancer, and age-related inflammation (inflammaging). These cells interact with stromal cells, activate the complement cascade, and perpetuate inflammation, highlighting their emerging therapeutic significance. We review the latest advances in the biology and pathological roles of GZMK+CD8+ T cells, and discuss the potential of targeting their dysregulated activities to treat chronic inflammation and malignancies.

Terekhova et al. perform single-cell RNA sequencing on >300 samples between 25 and 85 years to comprehensively profile immune changes throughout aging. This resource revealed 12 subpopulations that c...

Numerous studies have focused on the molecular regulation of perforin (PFP) and granzyme B (GZMB) expression by activated cytotoxic T lymphocytes (CTLs), but little is known about the molecular facto...