Studies carried out during the last few decades have consistently shown that cell surface MHC class I (MHC-I) molecules are endowed with functions unrelated with antigen presentation. These include ...cis–trans-interactions with inhibitory and activating KIR and LILR, and cis-interactions with receptors for hormones, growth factors, cytokines, and neurotransmitters. The mounting body of evidence indicates that these non-immunological MHC-I functions impact clinical and biomedical settings, including autoimmune responses, tumor escape, transplantation, and neuronal development. Notably, most of these functions appear to rely on the presence in hematopoietic and non-hematopoietic cells of heavy chains not associated with β2m and the peptide at the plasma membrane; these are known as open MHC-I conformers. Nowadays, open conformers are viewed as functional cis-trans structures capable of establishing physical associations with themselves, with other surface receptors, and being shed into the extracellular milieu. We review past and recent developments, strengthening the view that open conformers are multifunctional structures capable of fine-tuning cell signaling, growth, differentiation, and cell communication.
Antigen-driven human effector-memory CD8+ T cells expressing low levels of the CD8β chain have been previously described. However, little is known on a possible antigen-independent trigger. We have ...examined the impact that IL-15 has on the expression of CD8β on purified human naïve CD8+ T cells after CFSE labeling and culture with IL-15. As expected, IL-15 induced naïve CD8+ T cells to proliferate and differentiate. Remarkably, the process was associated with a cell-cycle dependent down-modulation of CD8β from the cell surface, leading to the generation of CD8αβ low and CD8αβ − (i.e., CD8αα) T cells. In contrast, expression of the CD8α chain remained steady or even increased. Neither IL-2 nor IL-7 reproduced the effect of IL-15. Determination of mRNA levels for CD8α and CD8β isoforms by qPCR revealed that IL-15 promoted a significant decrease in mRNA levels of the CD8β M-4 isoform, while levels of the M-1/M-2 isoforms and of CD8α increased. Noteworthy, CD8+ T cell blasts obtained after culture of CD8+ T cells with IL-15 showed a cell-cycle dependent increase in the level of the tyrosine kinase Lck, when compared to CD8+ T cells at day 0. This study has shown for the first time that IL-15 generates CD8αα + αβ low and CD8αα + αβ − T cells containing high levels of Lck, suggesting that they may be endowed with unique functional features.
Natural mineral (thermal) waters have been used for centuries as treatment for various diseases. However, the scientific background of such therapeutic action is mostly empiric and based on knowledge ...acquired over time. Among the various types of natural mineral waters, sulfurous thermal waters (STWs) are the most common type in the center of Portugal. STWs are characterized by high pH, poor mineralization, and the presence of several ions and salts, such as bicarbonate, sodium, fluoride, silica, and carbonate. Furthermore, these waters are indicated as a good option for the treatment of various illnesses, namely respiratory diseases (e.g., allergic rhinitis, asthma, and chronic obstructive pulmonary disease). From the sulfide species present in these waters, hydrogen sulfide (H
S) stands out due to its abundance. In healthy conditions, H
S-related enzymes (e.g., cystathionine β-synthase and cystathionine γ-lyase) are expressed in human lungs, where they have mucolytic, antioxidant, anti-inflammatory, and antibacterial roles, thus contributing to airway epithelium homeostasis. These roles occur mainly through S-sulfhydration, a post-translational modification through which H
S is able to change the activity of several targets, such as ion channels, second messengers, proteins, among others. However, in respiratory diseases the metabolism of H
S is altered, which seems to contribute somehow to the respiratory deterioration. Moreover, H
S has been regarded as a good biomarker of airway dysfunction and severity, and can be measured in serum, sputum, and exhaled air. Hence, in this review we will recapitulate the effects of STWs on lung epithelial-immune crosstalk through the action of its main component, H
S.
MHC class I molecules regulate brain development and plasticity in mice and HLA class I molecules are associated with brain disorders in humans. We investigated the relationship between ...plasma‐derived soluble human HLA class I molecules (sHLA class I), HLA class I serotypes and dementia. A cohort of HLA class I serotyped elderly subjects with no dementia/pre‐dementia (NpD, n = 28), or with dementia (D, n = 28) was studied. Multivariate analysis was used to examine the influence of dementia and HLA class I serotype on sHLA class I levels, and to compare sHLA class I within four groups according to the presence or absence of HLA‐A23/A24 and dementia. HLA‐A23/A24 and dementia, but not age, significantly influenced the level of sHLA class I. Importantly, the concurrent presence of HLA‐A23/A24 and dementia was associated with higher levels of sHLA class I (p < 0.001). This study has shown that the simultaneous presence of HLA‐A23/HLA‐A24 and dementia is associated with high levels of serum sHLA class I molecules. Thus, sHLA class I could be considered a biomarker of neurodegeneration in certain HLA class I carriers.
There is increasing evidence that in humans the adaptive immunological system can influence cognitive functions of the brain. We have undertaken a comprehensive immunological analysis of lymphocyte ...and monocyte populations as well as of HLA molecules expression in a cohort of elderly volunteers (age range, 64-101) differing in their cognitive status. Hereby, we report on the identification of a novel signature in cognitively impaired elderly characterized by: (1) elevated percentages of CD8+ T effector-memory cells expressing high levels of the CD45RA phosphate receptor (Temra
); (2) high percentages of CD8+ T cells expressing high levels of the CD8β chain (CD8β
); (3) augmented production of IFNγ by
activated CD4+ T cells. Noteworthy, CD3+CD8+ Temra
and CD3+CD8β
cells were associated with impaired cognition. Cytomegalovirus seroprevalence showed that all volunteers studied but one were CMV positive. Finally, we show that some of these phenotypic and functional features are associated with an increased frequency of the HLA-B8 serotype, which belongs to the ancestral haplotype HLA-A1, Cw7, B8, DR3, DQ2, among cognitively impaired volunteers. To our knowledge, this is the first proof in humans linking the amount of cell surface CD45RA and CD8β chain expressed by CD8+ Temra cells, and the amount of IFNγ produced by
activated CD4+ T cells, with impaired cognitive function in the elderly.
Sulfurous thermal waters (STWs) are used as a complementary treatment for allergic rhinitis. However, there is scant data on the effects of STW on nasal epithelial cells, and in vitro models are ...warranted. The main aim of this study was to evaluate the dose and time effects of exposure to 3D nasal inserts (MucilAir
-HF allergic rhinitis model) with STW or isotonic sodium chloride solution (ISCS) aerosols. Transepithelial electrical resistance (TEER) and histology were assessed before and after nebulizations. Chemokine/cytokine levels in the basal supernatants were assessed by enzyme-linked immunosorbent assay. The results showed that more than four daily nebulizations of four or more minutes compromised the normal epithelial integrity. In contrast, 1 or 2 min of STW or ISCS nebulizations had no toxic effect up to 3 days. No statistically significant changes in release of inflammatory chemokines MCP-1/CCL2 > IL-8/CXCL8 > MIP-1α/CCL3, no meaningful release of "alarmins" (IL-1α, IL-33), nor of anti-inflammatory IL-10 cytokine were observed. We have characterized safe time and dose conditions for aerosol nebulizations using a novel in vitro 3D nasal epithelium model of allergic rhinitis patients. This may be a suitable in vitro setup to mimic in vivo treatments of chronic rhinitis with STW upon triggering an inflammatory stimulus in the future.
Understanding the rationale for the generation of a pool of highly differentiated effector memory CD8
T cells displaying a weakened capacity to scrutinize for peptides complexed with major ...histocompatibility class I molecules
their T cell receptor, lacking the "signal 2" CD28 receptor, and yet expressing a highly diverse array of innate receptors, from natural killer receptors, interleukin receptors, and damage-associated molecular pattern receptors, among others, is one of the most challenging issues in contemporary human immunology. The prevalence of these differentiated CD8
T cells, also known as CD8
CD28
, CD8
KIR
, NK-like CD8
T cells, or innate CD8
T cells, in non-lymphoid organs and tissues, in peripheral blood of healthy elderly, namely centenarians, but also in stressful and chronic inflammatory conditions suggests that they are not merely end-of-the-line dysfunctional cells. These experienced CD8
T cells are highly diverse and capable of sensing a variety of TCR-independent signals, which enables them to respond and fine-tune tissue homeostasis.
Abstract During the last years several authors have described a small population of CD8+ T cells expressing NK receptors (NKRs). Although their origin remains largely unknown, we have recently ...demonstrated that IL-15 is capable of inducing NKR expression in purified human CD8+CD56− T cells. In this study we show that IL-15-driven NKR induction in CD8+ T cells was linked with CD56 de novo acquisition, consistent with an effector-memory phenotype, increased anti-apoptotic levels, high granzyme B/perforin expression and with the ability of displaying in vitro NK-like cytotoxicity. Interestingly, dissection of NKR functional outcome in IL-15-cultured CD8+ T cells revealed: (i) that NKG2D cross-linking was able per se to upregulate degranulation levels and (ii) that KIR and NKG2A cross-linking upregulated secretion of cytokines such as IFN-γ, TNF-α, IL-1β and IL-10. These results suggest that IL-15 is capable of differentiating CD8+ T cells into NK-like T cells displaying a regulatory phenotype.
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by overproduction of red blood cells. We have performed a comprehensive characterization of blood immune cells for expression of ...naïve and memory receptors as well as β
2
m-associated and β
2
m-free MHC class I heavy chains, also known as closed and open conformers, respectively, in PV patients and age-matched controls (CTR). We show that the peripheral CD3
+
CD8
+
T cell pool in PV patients is clearly divided into two discrete populations, a more granular CD3
+
CD8
high
T cell population enriched in effector-memory CD45RA
+
T cells (CD8
+
T
EMRA
) when compared to CTR (
P
< 0.001), and a less granular CD3
+
CD8
int
T cell population that is completely absent in the CTR group (78 vs. 0%,
P
< 0.001) and is a mixture of naïve (CD8
+
T
N
) and CD8
+
T
EMRA
cells expressing intermediate levels of CD28, i.e., CD3
+
CD8
int
CD28
int
. While the percentage of CD3
+
CD8
int
T
N
cells correlated positively with the number of erythrocytes, the percentage of CD3
+
CD8
int
T
EMRA
correlated negatively with the number of platelets. Finally, we report that PV patients’ lymphocytes and monocytes display lower levels of closed (W6/32
+
) MHC-I conformers at the cell surface while exhibiting increased amounts of open (HC-10
+
) MHC-I conformers. The implications of this distinctive immune signature are discussed.
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