“It is generally accepted that replicative senescence of T-cells during aging and/or chronic infection is a major contributing factor in immunological failure. It involves both the host’s capacity to respond to infections and the development of long-term immune memory.”
I had the chance to test my cellular immune status. What I learned, lead eventually to a correct diagnosis and treatment.
T-cells 76.0 % 61 – 84
T-cells 2008 / ul 920 – 2580
CD45RA+ naive T – cells 41.0 % 30 – 60
CD45RA+ naive T – cells 822 / ul 300 – 1200
CD45RA- memory T- cells 59.0 % 37 – 70
CD45RA- memory T- cells 1185 / ul 300 – 1300
CD4- helper cells 40.0 % 32 – 60
CD4- helper cells 1043 / ul 550 – 1460
CD45RA+naive 26.0 % 19 – 58
CD31+ 64.0 % CD45RA > 49
CD25++/CD127- T-reg cells 11.0 % 4 – 10
CD25++/CD127 -T-reg cells 115 / ul 35 – 120
CD39 + Treg 59.0 %
CD8 – Lymphocytes 33 % 23 – 40
CD8 – Lymphocytes 870 / ul 280 – 930
CD8+/CD28+ (zytotox.) 41.0 % 57 – 94
CD8+/CD28+ (Zytotox.) 358 /ul 130 – 450
CD8+/CD28- 59.0 % (av.25%) 6 – 43
CD8+/CD28- 512 /ul 20 – 300
CD4+/CD8+ ratio 1.20 1 – 3
CD4+/CD8+ T cells 0.9 % < 5
CD4+/CD8+ T cells 16.0 % 7 – 21
Nk cells 4 % 10 – 30
Nk cells 105 /ul 210 – 740
activated NK- cells 5.9 % < 17
activated Nk – cells 6 /ul < 40
HLADR+ /CD3+ 7 % < 11
HLADR+/CD3+ 191 /ul < 230
CD25+/CD3+ 20 % < 18
CD25+/CD3+ 518 /ul < 230
NK cells are decreased. T-regulatory CD4+CD25+ (CD127-) FoxP3 are not significantly increased and IL-10, which usually goes along with T-reg function and suppression, is on the lower side. The CD25+CD3+ is generally considered an early activation marker for pre-activated T cells. (CD25 the alpha chain of the IL-2 receptor required for T-reg function). Remarkable is the ratio of increased CD8+CD28- verses low CD8+CD28+ cells.
CD8(+) T cells contribute to resistance against intracellular infections with certain viral, protozoan, and intracellular bacterial pathogens. CD8+ T cells receive activation signal when their T-cell receptor (TCR) recognizes MHC-I-bound peptide antigen, presented on the surface of professional antigen-presenting cells (pAPCs), namely dendritic cells (DCs) and macrophages/monocytes. However, this interaction is low-affinity and requires a large number of TCR ‘hits’ so in the majority of cases the stimulation via TCR alone is unable to sustain optimal activation of naive and memory CD8+ T cells. Therefore a second (co-stimulatory) signal is generally indispensable for their full activation and survival. The best defined (but not the sole) co-stimulus is provided by the interaction of CD28 (on the surface of the T cell). The co-stimulatory signals, which are mediated via CD28, are of critical importance in the triggering of appropriate T cell responses. Under persistent antigenic stimulation several activation cycles of CD8+CD28 cells occur and with each repetitive stimulation/proliferation round, CD28 expression is progressively and irreversibly down-regulated on the surface of CD8+ T cells, eventually leading to the accumulation of highly antigen-experienced CD8+ CD28− T cells with critically shortened telomeres.
The accumulated CD8+ T cell clones are typically described as “exhausted” and “senescent”. These two terms are often used interchangeably with regard to aging T cells, some argue they are distinct. Replicative senescence refers to cells that no longer divide in response to typical stimuli. (Telomere length and telomerase activity have been often considered the “gold standard” markers of cellular senescence, but differ markedly between murine and human T cells). In contrast to cell senescence, T cell exhaustion refers to the progressive decline of T cell “effectiveness” during successive rounds of re-stimulation. Exhaustion is seen mostly under situations of continuous antigenic stimulation as occurs with persistent, chronic infections, where the cells are continuously exposed to antigens.
Note: initially, the replicative history of CD8+ T cells was only defined by the loss of CD28, later it was found that with the decrease of CD28, the expression of CD57 increases. The expression of CD57 found on T-lineage lymphocytes is now also considered a marker for replicative senescence (“clonal exhaustion”). This proliferative defect had been shown in all lymphocyte subsets, which express CD57 (CD4+ and CD8+ T lymphocytes and NK cells) and with some relevant exception, was not overcome by addition of IL-2 or IL-15. So keep in mind that the term ‘CD8+ T cells’ is often used to describe all, ‘CD8+ CD57+’and ‘CD8+ CD28-‘ T lymphocytes and in various papers these T cells are also defined as ‘CD8+CD28- regulatory cells’ or ‘suppressor cells’, ‘CD8+/high CD57+’ or sometimes as ‘CD8+ CD28- CD57+’, but actually all of these cases deal with the clonally expanded CD8+ T cells generated in response to chronic antigenic stimulation.
There is plenty of evidence that CD8+CD28- T-cell (CD57) population plays a significant role in various diseases or conditions associated with chronic immune activation such as cancer, chronic infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8+ CD28 T cells are virtually absent in the umbilical cord and neonatal blood and gradually expand throughout life; by 80 years of age 50–60% of CD8+ T cells are CD28−.
CD8+CD28- T regulatory lymphocytes are also almost constantly present and functional in human tumors, being able to inhibit both T cell proliferation and cytotoxicity. CD4+CD25- T regulatory lymphocytes associate with CD8+CD28- T regulatory cells, so that the immunosuppressive activity of tumor-infiltrating regulatory T cell subsets, altogether considered, may become predominant. It was also found that CD8+CD28− lymphocytes have regulatory functions in controlling susceptibility to an autoimmune disease. In an experimental autoimmune encephalomyelitis model, CD8+CD28− cells suppressed disease activity. In transplantation or in RA, the accumulation of these exhausted CTL may contribute to tolerance and downregulation of the alloimmune response, and be reversing their senescent state may have deleterious effects. Just a few weeks ago another interesting article was published on T-cell exhaustion, co-stimulation and clincical autcome in autoimmunity and infection
High proportions of CD8+CD28- subpopulation and low CD8+CD28+/CD8+CD28- T cells ratio were observed in hepatitis B e antigen- (HBeAg-) positive individuals as compared with that in HBeAg-negative subjects. Chronic hepatitis C infection has also been associated with clonal expansions of CD8+CD28- cells and is associated with cirrhosis and fibrosis in this disease. In sarcoidosis, the blood CD8+CD28 null subset may be a new biomarker for disease severity. Group G Streptococcal Bacteraemia is an opportunistic infection associated with immune-senescence. Increased proportions of CD57+CD8+ T cells have also been reported in those infected with human parvovirus, measles, pulmonary tuberculosis, and toxoplasmosis. Chagasic patients throughout the spectrum of chronic clinical forms of the infection have significantly higher mean frequencies of CD4+CD28– and CD8+CD28– T cells, as compared with non-chagasic individuals. Chagas disease is caused by single-celled parasites (protozoa) called trypanosomes, also often called the “new AIDS of the Americas”.
Although several of those conditions characterized by chronic antigenic stimulation may result in such an immune state, this underlying pathogenesis is a hallmark of untreated HIV infection. CD8+ CD28- T cells in the blood of HIV patients constituted 74% of CD8+ cells compared to 25% in normal subjects. The CD8+CD28− T cell accumulation during HIV-1 infection may contribute to accelerated inflammatory reactions and immune activation and lack of CD28 expression on HIV- specific cytotoxic T lymphocytes is associated with disease progression. In HIV disease, the presence of proliferation-incompetent HIV-specific CD8+ T cells is the result, not the cause, of uncontrolled viral replication. In SIV mac251‐infected macaques, as in HIV‐l‐infected patients, the amplification of these lmmunodeficient CD8+CD28‐ and CD8+CD57‐ T cells is correlated to the evolution of AIDS.
It is therefore generally accepted that replicative senescence of T-cells during aging and/or chronic infection is a major contributing factor in immunological failure. It involves both the host’s capacity to respond to infections and the development of long-term immune memory (especially by vaccination). This associated immune deficiency can be ubiquitous. For example, a problem of infections in the elderly is that they frequently present with non-specific signs and symptoms, and clues of focal infection (antibodies) are often absent or obscured. Ultimately, this provides problems in diagnoses, such as recognizing serious infections and sepsis. Fever may be blunted or absent and some may be hypothermic — a poor prognostic sign.
Back to my test results: the ratio of increased CD8+CD28- verses low CD8+CD28+ cells show a considerable functionally exhausted immune system. At the same time, the pre-activated CD25+/CD3+ cells point to a highly activated immune system. Remember: “Exhaustion is seen mostly under situations of continuous antigenic stimulation as occurs with persistent, chronic infections, where the cells are continuously exposed to antigens.”
To be continued…..
References
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PDF (Great pics!)
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