The thymus is known to atrophy during infections; however, a systematic study of changes in thymocyte subpopulations has not been performed. This aspect was investigated, using multi-color flow cytometry, during oral infection of mice with Salmonella Typhimurium (S. Typhimurium). The major highlights are: First, a block in the developmental pathway of CD4−CD8− double negative (DN) thymocytes is observed. Second, CD4+CD8+ double positive (DP) thymocytes, mainly in the DP1 (CD5loCD3lo) and DP2 (CD5hiCD3int), but not DP3 (CD5intCD3hi), subsets are reduced. Third, single positive (SP) thymocytes are more resistant to depletion but their maturation is delayed, leading to accumulation of CD24hiCD3hi SP. Kinetic studies during infection demonstrated differences in sensitivity of thymic subpopulations: Immature single positive (ISP) > DP1, DP2 > DN3, DN4 > DN2 > CD4+ > CD8+. Upon infection, glucocorticoids (GC), inflammatory cytokines, e.g. Ifnγ, etc are induced, which enhance thymocyte death. Treatment with RU486, the GC receptor antagonist, increases the survival of most thymic subsets during infection. Studies with Ifnγ−/− mice demonstrated that endogenous Ifnγ produced during infection enhances the depletion of DN2-DN4 subsets, promotes the accumulation of DP3 and delays the maturation of SP thymocytes. The implications of these observations on host cellular responses during infections are discussed.

The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediated by T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex with major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding of cognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. In addition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates T cell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the main positive costimulatory receptor on naïve T cells; upon activation, CTLA4 is induced but reduces T cell activation. Further studies led to the identification of additional negative costimulatory receptors known as checkpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discovery of checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) which reduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, the mechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.

Nontyphoidal disease contributes toward significant morbidity and mortality across the world. Host factors, including gamma interferon, tumor necrosis factor alpha, and gut microbiota, significantly influence the outcome of pathogenesis. However, the entire repertoire of host protective mechanisms contributing to pathogenicity is not completely appreciated. Here, we investigated the roles of receptor guanylyl cyclase C (GC-C), which is predominantly expressed in the intestine and regulates intestinal cell proliferation and fluid-ion homeostasis. Mice deficient in GC-C () displayed accelerated mortality compared with that for wild-type mice following infection via the oral route, even though both groups possessed comparable systemic infection burdens. Survival following intraperitoneal infection remained similar in both groups, indicating that GC-C offered protection via a gut-mediated response. The serum cortisol level was higher in mice than wild-type () mice, and an increase in infection-induced thymic atrophy with a loss of immature CD4 CD8 double-positive thymocytes was observed. Accelerated and enhanced damage in the ileum, including submucosal edema, epithelial cell damage, focal tufting, and distortion of the villus architecture, was seen in mice concomitantly with a larger number of ileal tissue-associated bacteria. Transcription of key mediators of-induced inflammation (interleukin-22/Reg3β) was altered in mice in comparison to that in mice. A reduction in fecal lactobacilli, which are protective against infection, was observed in mice. mice cohoused with wild-type mice continued to show reduced amounts of lactobacilli and increased susceptibility to infection. Our study, therefore, suggests that the receptor GC-C confers a survival advantage during gut-mediated serovar Typhimurium pathogenesis, presumably by regulating effector mechanisms and maintaining a beneficial microbiome.

Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

Copper(II) and zinc(II) β‐diketonates of N,N‐donor ligands, viz. [Cu(dppz)(cur)](NO3) (1), [Cu(acdppz)(cur)](NO3) (2), [Cu(acdppz)(acac)](NO3) (3), [Zn(dppz)(cur)](NO3) (4) and [Zn(acdppz)(cur)](NO3) (5), where dppz is dipyrido[3,2‐a:2’,3’‐c]phenazine, acdppz is 11‐(9‐acridinyl)dipyrido[3,2‐a:2’,3’‐c]phenazine, cur and acac are mono‐deprotonated curcumin (Hcur) and acetyl acetone (Hacac), were synthesized, characterized and their photocytotoxicity studied. An analogue of complex 3, viz. [Cu(acdppz)(acac)(H2O)]Cl1/2(NO3)1/2 (3 a), structurally characterized by X‐ray crystallography, has a cationic complex in square‐pyramidal geometry with CuN2O3 core with an axial aqua ligand. Complexes 1, 2, 4 and 5 displayed emission at ∼520 nm (λexc: 430 nm) in dimethyl sulfoxide (DMSO) giving a fluorescence quantum yield value within 0.01‐0.06. The complexes, in contrast to free curcumin, were fairly stable in cellular media up to 36 h, with no apparent degradation of the bound curcumin. The complexes were photocytotoxic (IC50: 0.3 ‐ 4.5 μM) in human cervical cancer (HeLa), breast cancer (MCF‐7) and liver cancer (HepG2) cells. The apoptotic cell death is due to reactive oxygen species formation. Complexes 2 and 5 showed significant uptake in HeLa cells, localizing predominantly in the cytoplasm. Mechanistic data from the pUC19 DNA photocleavage study suggest involvement of acridine and curcumin in photo‐generation of singlet oxygen and hydroxyl radicals as the ROS in light of 400–700 nm.