Th17 and CD24hiCD27+ regulatory B lymphocytes are biomarkers of response to biologics in rheumatoid arthritis.

BACKGROUND: The aim was to describe the regulatory B and T cells (Breg and Treg) and T helper 17 (Th17) lymphocytes before and under treatment with biologic drugs, and to assess their potential predictive value as biomarkers of response in rheumatoid arthritis (RA). METHODS: This was a non-randomised, single-centre, prospective study. Patients with active RA (American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010) who required the initiation or switch to any biologic drug except rituximab were included. The main judgement criterion was the frequency and absolute number of CD24hiCD27+ Breg and CD24hiCD38hi T2/Breg cells, CD25hiCD127low Treg and CD45RA-CD161+CCR6+ Th17 cells measured at inclusion in both patients and controls, and after 1, 3 and 6 months of treatment (M1, M3 and M6) in patients with RA, and compared with the M6 response to treatment (EULAR response and Disease Activity Score in 28 joints (DAS28) remission). RESULTS: Thirty-one patients with RA and 17 controls were included. There was a reduction in T2/Breg frequency at M0 in patients (p < 0.001) and absolute numbers (p = 0.014) and in immunopositive vs. immunonegative RA (p = 0.016). DAS28 remission at M6 was associated with increased frequency of Treg (p = 0.01). A higher level of CD24hiCD27+ Breg at baseline was associated with DAS28 remission at M6 (p = 0.04) and a good EULAR response at M6 for abatacept-treated patients (p = 0.01). A lower M0 level of Th17 was associated with a good EULAR response at M6 (p = 0.007), notably under anti-cytokine drugs (p = 0.048). CONCLUSIONS: Altogether, these data, although preliminary, suggest that phenotyping of T and B cells has potential value for the stratification of biologic drugs, notably with respect to choosing between abatacept and anti-cytokine blockade.

Paradoxical articular manifestations in patients with inflammatory bowel diseases treated with infliximab.

INTRODUCTION: Articular involvement is the most common extraintestinal manifestation associated with inflammatory bowel diseases (IBDs). Manifestations are 'paradoxical' when they occur during treatment, notably with anti-tumor necrosis factor (anti-TNF) drugs, which are expected to prevent or treat them. The aim of this study was to assess the frequency, characteristics, and associated factors of paradoxical articular manifestations in patients with IBD treated with anti-TNF. PATIENTS AND METHODS: In this prospective single-center study, an examination by a rheumatologist was systematically offered to all patients with IBD treated with infliximab (IFX) to assess the prevalence of articular manifestations and distinguish between those related to treatment and those associated with intestinal disease. Paradoxical manifestations were defined as the occurrence of articular manifestations (excluding induced lupus and hypersensitivity reactions) during anti-TNF therapy in patients with intestinal remission. Measures of biological inflammatory, immunological markers, HLA-B27 allele, IFX trough levels, and anti-IFX antibody (Ab) were performed for all patients. RESULTS: Between May 2013 and April 2014, 65 patients with Crohn's disease and 15 with patients ulcerative colitis treated with IFX were included. The median duration of anti-TNF therapy was 66 months [quartile (Q)1=23 months-Q3=81 months]. Articular manifestations were observed in 50 (62%) patients treated with IFX. Eleven percent (n=9) were considered to be associated with IBD and 16% (n=13) to be associated with anti-TNF therapy. Among articular manifestations associated with anti-TNF therapy, nine (11%) patients were considered paradoxical, two (2%) as drug-induced lupus, and two (2%) as a hypersensitivity reaction. Among the nine patients with paradoxical manifestations, all had Crohn's disease in clinical remission, three patients presented a spondyloarthropathy, and three developed associated paradoxical psoriasis. No patient discontinued anti-TNF because of the articular manifestations. Methotrexate was effective on articular symptoms in two of the three treated patients with paradoxical manifestations. No clinical or biological factors, including IFX trough levels, were associated with the occurrence of paradoxical manifestations. CONCLUSION: Paradoxical articular manifestations in IBD patients treated by anti-TNF are common, affecting more than 10% of patients. These events are generally mild and do not need discontinuation of anti-TNF therapy.

Increased tumor infiltration by mucosal-associated invariant T cells correlates with poor survival in colorectal cancer patients.

The infiltration of tumors by lymphocytes is a prognosis factor in colorectal cancer (CRC). The magnitude and quality of this infiltration have emerged as important component of the clinical outcome in these patients. Specifically, markers associated with functional cell-mediated immunity, i.e., a Th1 immune response, are independent markers of better prognosis, whereas Th17-associated components are deleterious and correlate with poorer survival. Mucosal-associated invariant T (MAIT) cells are a recently described T cell subset with tissue-homing properties. They display a restricted TCR repertoire specific for widely conserved microbial ligands, and display anti-bacterial properties upon release of Th1-like, Th17-like, and/or cytotoxic granules. MAIT-cell-specific transcripts have been found in kidney and brain cancer, but have not been studies in other sites. In this study, we retrospectively analyzed by confocal microscopy the presence of MAIT cells within colorectal tumors as compared with paired healthy tissues. We observed a significant although variable increase, both in density and in proportion of overall tumor-infiltrating T lymphocytes inside the tumors. Importantly, survival curves as well as multivariate analysis showed that patients displaying a higher recruitment of MAIT cells in their tumor, as compared with the neighboring healthy tissue, showed a less favorable clinical outcome. This study suggests that including MAIT-cell-specific markers or transcripts in the analysis of tumor-infiltrating lymphocytes could be a benefit to the diagnosis and follow-up of CRC patients.

Factors involved in CLL pathogenesis and cell survival are disrupted by differentiation of CLL B-cells into antibody-secreting cells.

Recent research has shown that chronic lymphocytic leukemia (CLL) B-cells display a strong tendency to differentiate into antibody-secreting cells (ASCs) and thus may be amenable to differentiation therapy. However, the effect of this differentiation on factors associated with CLL pathogenesis has not been reported. In the present study, purified CLL B-cells were stimulated to differentiate into ASCs by phorbol myristate acetate or CpG oligodeoxynucleotide, in combination with CD40 ligand and cytokines in a two-step, seven-day culture system. We investigated (i) changes in the immunophenotypic, molecular, functional, morphological features associated with terminal differentiation into ASCs, (ii) the expression of factors involved in CLL pathogenesis, and (iii) the expression of pro- and anti-apoptotic proteins in the differentiated cells. Our results show that differentiated CLL B-cells are able to display the transcriptional program of ASCs. Differentiation leads to depletion of the malignant program and deregulation of the apoptosis/survival balance. Analysis of apoptosis and the cell cycle showed that differentiation is associated with low cell viability and a low rate of cell cycle entry. Our findings shed new light on the potential for differentiation therapy as a part of treatment strategies for CLL.

Increased MerTK expression in circulating innate immune cells of patients with septic shock.

PURPOSE: A new pathway of three protein tyrosine kinase receptors, namely, the TAM receptor family [Tyro-3, Axl and Mer tyrosine kinase (MerTK)], has recently been described to negatively control immune responses. The objective of this prospective, observational, clinical study was to investigate the expression patterns of TAM receptors in circulating white blood cells collected from patients with septic shock. METHODS: The expression of TAM receptors was measured by flow cytometry in circulating leukocytes from patients with septic shock sampled on days (D) 1-2 (n = 47) and D3-4 (n = 37) after the onset of shock, severe trauma patients at D1-2 after trauma (n = 51) and healthy individuals (n = 23). RESULTS: On D1-2 after injury, MerTK was overexpressed in monocytes and neutrophils collected from patients with septic shock in comparison with those collected from healthy volunteers and trauma patients. This phenomenon was also observed for mRNA. Conversely, the expression of Tyro-3 and Axl was higher in monocytes from trauma patients versus healthy volunteers or those in septic shock. MerTK expression between D1-2 and D3-4 remained elevated in patients suffering from septic shock who died or developed an intensive care unit-acquired infection, whereas it decreased in patients who recovered uneventfully. This in vivo observed expression pattern was reproduced ex vivo after the incubation of healthy volunteer cells with plasma from septic shock or trauma patients. CONCLUSIONS: MerTK expression in circulating innate immune cells is increased in patients with septic shock in comparison with healthy volunteers and trauma patients. Persistent MerTK overexpression after septic shock is associated with adverse outcome. The role of this family of receptors in the pathophysiology of injury-induced immune dysfunctions deserves to be specifically investigated.

Assessment of cellular immune parameters in paediatric toxic shock syndrome: a report of five cases.

Toxic shock syndrome (TSS) and septic shock (SS) share many clinical signs of an exacerbated inflammatory response. In this report, we investigated whether TSS presents similar features of delayed immunosuppression as described in SS. Five children with TSS from paediatric intensive care units in a university hospital were monitored. TSS cases were defined by the association of standardized clinical signs of TSS and confirmed by measurement of specific Vbeta expansions corresponding to toxin gene profile of the isolated strains. As in SS, an increased percentage of circulating regulatory T cells (Treg) was observed in patients with TSS. However, in contrast to SS, neither lymphopenia nor decreased HLA-DR expression on monocytes was measured. In conclusion, whereas SS and TSS exhibited similar clinical presentation, the present observation suggests that respective pathophysiological mechanisms induce different immune alterations. Future studies must isolate and better characterize the phenotypic and functional properties of Treg subsets during TSS to understand the mechanisms sustaining their increase, especially the putative role of superantigens.

Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma.

OBJECTIVE: Major trauma is characterized by a pro-inflammatory response, followed by an immunosuppression. Recently, in trauma patients, the lack of recovery of monocyte Human Leukocyte Antigen DR (mHLA-DR, a biomarker of ICU-acquired immunosuppression) between days 1-2 and days 3-4 has been demonstrated to be independently associated with sepsis development. The main objective of this study was to determine whether early measurements of IL-6 (interleukin-6) and IL-10 plasma concentrations (as markers of initial severity) could improve, in association with mHLA-DR recovery, the prediction of sepsis occurrence in severe trauma patients. DESIGN: Prospective observational study over 24 months in a Trauma ICU at university hospital. PATIENTS: Trauma patients with an ISS over 25 and age over 18 were included. MEASUREMENTS AND MAIN RESULTS: mHLA-DR was assessed by flow cytometry, IL-6 and IL-10 concentrations by ELISA. 100 consecutive severely injured patients were monitored (mean ISS 37±10). 37 patients developed sepsis. IL-6 concentrations and slope of mHLA-DR expression between days 1-2 and days 3-4 were significantly different between septic and non-septic patients. IL-10 was not detectable in most patients. After adjustment for usual clinical confounders, when assessed as a pair, multivariate logistic regression analysis revealed that a slope of mHLA-DR expression (days 3-4/days 1-2)≤1.1 and a IL-6 concentration ≥ 67.1 pg/ml remained highly associated with the development of sepsis (adjusted OR 18.4, 95% CI 4.9; 69.4, p = .00002). CONCLUSIONS: After multivariate regression logistic analysis, when assessed as a pair, a high IL-6 concentration and a persistent mHLA-DR decreased expression were found to be in relation with the development of sepsis with the best predictive value. This study underlines the usefulness of daily monitoring of immune function to identify trauma patients at a high risk of infection.

Persistent high level of circulating midregional-proadrenomedullin and increased risk of nosocomial infections after septic shock.

BACKGROUND: Risk stratification could represent a major improvement in critically ill patients' management. The objective of this study is to evaluate the association between concentrations of four circulating prohormones (C-terminal-provasopressin, midregional-proadrenomedullin (MR-proADM), midregional-proatrial natriuretic peptide, and C-terminal- proendothelin-1) and the occurrence of nosocomial infections (NIs) in septic shock patients. METHODS: We performed an observational, clinical study with septic shock patients (n = 98) recruited from adult intensive care units in a university hospital. Prohormone concentrations were assessed three times within the first week after the onset of septic shock using an immunoluminometric assay. RESULTS: Significantly elevated plasmatic MR-proADM concentrations were measured in patients who went on to develop NIs in comparison with patients who remain infection free (p = 0.043). No differences were observed for the other three prohormone concentrations. CONCLUSIONS: Elevated plasmatic MR-proADM concentration is associated with the development of secondary NIs after septic shock. This information, if confirmed in a larger group of patients, could represent a major advance in the monitoring of intensive care unit patient infectious risk.

Assessment of plasmatic immunoglobulin G, A and M levels in septic shock patients.

Polyvalent immunoglobulin (Ig) therapy has been tested as adjunctive treatment in sepsis and septic shock, but its efficacy is still a matter of debate. This has been explained because clinical trials were mostly performed on small numbers of patients. Moreover, the endogenous level of circulating Ig in patients was never taken into account. In this study, plasmatic Ig classes and protein concentrations were measured at Days (D) 1-2, D3-4 and D5-7 in 62 septic shock patients. At D1-2 as well as at D3-4, patients presented with a significant reduction of plasmatic IgG concentrations. Indeed, at D1-2, 61% of the patients had IgG level below the lowest limit of our age-matched reference values. Plasmatic IgM levels were decreased as well in comparison with reference values from the lab whereas IgA concentrations were not modified. Circulating IgG and IgM concentrations tends to increase overtime. Indeed, at D5-7, most patients (61%) had IgG and IgM levels within the range of normal values. These alterations did not appear to be associated with increased mortality, morbidity or severity after septic shock. However, at D1-2 and D3-4, decreased circulating Ig level was significantly correlated with reduced plasmatic protein concentrations. Overall, our results suggest that an apparent hypogammaglobulinemia is present at D1-2 and D3-4 in septic shock patients, which seems to be related with reduced circulating protein concentration after septic shock. These results need to be confirmed in a larger cohort of patients.

Flow cytometry developments and perspectives in clinical studies: examples in ICU patients.

Septic syndromes represent a major, although largely under-recognized, healthcare problem worldwide accounting for thousands of deaths every year. Although flow cytometry (FCM) remains a relatively confidential diagnostic tool, it is useful at every step of intensive care unit (ICU) patients' management. This review will focus on biomarkers measurable by FCM on a routine standardized basis and usable for the diagnosis of sepsis and for prediction of adverse outcome, occurrence of secondary nosocomial infections or guidance of putative immunotherapy relative to innate and adaptive immune dysfunctions in ICU patients. Regarding early diagnosis of infection, neutrophil CD64 has been shown to be a highly sensitive and specific marker for systemic infection and sepsis in adults, neonates, and children. A diminished monocyte HLA-DR expression is a reliable marker for the development of monocyte anergy, secondary nosocomial infection, and death in critically ill patients. Finally, the measurement of an increased CD4(+)CD25(+)CD127(low) regulatory T cell percentage may represent a reliable marker for the diagnosis of lymphocyte dysfunctions in these patients. These stainings can be performed using lyse-no-wash methods and results are available within 1 h. Ideally, these biomarkers should be part of a panel helping to define ICU patients' immune status. In the specific clinical context of ICU patients' monitoring, the increasing potential of FCM is further illustrated by the use of the biomarkers listed above as stratification tools in preliminary clinical studies. The next critical step is to use these standardized FCM protocols in large multicentric clinical trials testing individualized immunotherapy. Importantly, many other markers of immune dysfunction are currently under development that could further enable the administration of targeted individualized therapy in ICU patients.

Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients.

INTRODUCTION: Septic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients. METHODS: This prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed. RESULTS: We observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4+ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration. CONCLUSIONS: These findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease.

Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma.

INTRODUCTION: Major trauma is characterized by an overwhelming pro-inflammatory response and an accompanying anti-inflammatory response that lead to a state of immunosuppression, as observed after septic shock. Diminished monocyte Human Leukocyte Antigen DR (mHLA-DR) is a reliable marker of monocyte dysfunction and immunosuppression. The main objective of this study was to determine the relation between mHLA-DR expression in severe trauma patients and the development of sepsis. METHODS: We conducted a prospective observational study over 23 months in a trauma intensive care unit at a university hospital. Patients with an Injury Severity Score (ISS) over 25 and age over 18 were included. mHLA-DR was assessed by flow cytometry protocol according to standardized protocol. Mann-Whitney U-test for continuous non-parametric variables, independent paired t test for continuous parametric variables and chi-square test for categorical data were used. RESULTS: mHLA-DR was measured three times a week during the first 14 days. One hundred five consecutive severely injured patients were monitored (ISS 38 ± 17, SAPS II 37 ± 16). Thirty-seven patients (35%) developed sepsis over the 14 days post-trauma. At days 1-2, mHLA-DR was diminished in the whole patient population, with no difference with the development of sepsis. At days 3-4, a highly significant difference appeared between septic and non-septic patients. Non- septic patients showed an increase in mHLA-DR levels, whereas septic patients did not (13,723 ± 7,766 versus 9,271 ± 6,029 antibodies per cell, p = .004). Most importantly, multivariate logistic regression analysis, after adjustment for usual clinical confounders (adjusted OR 5.41, 95% CI 1.42-20.52), revealed that a slope of mHLA-DR expression between days1-2 and days 3-4 below 1.2 remained associated with the development of sepsis. CONCLUSIONS: Major trauma induced an immunosuppression, characterized by a decrease in mHLA-DR expression. Importantly, after multivariate regression logistic analysis, persistent decreased expression was assessed to be in relation with the development of sepsis. This is the first study in trauma patients showing a link between the lack of immune recovery and the development of sepsis on the basis of the standardized protocol. Monitoring immune function by mHLA-DR measurement could be useful to identify trauma patients at a high risk of infection.

Proatrial natriuretic peptide is a better predictor of 28-day mortality in septic shock patients than proendothelin-1.

BACKGROUND: Septic shock is a major health care problem that affects a heterogeneous population of patients. To improve sepsis management, a key point is to decrease this heterogeneity by stratifying patients according to specific criteria, such as appropriate biomarkers. As the early phase of septic shock is characterized by cardiovascular dysfunction, precursors of vasoactive hormones represent interesting candidates. The objective of the present study was to concomitantly assess the predictive value of C-terminal proendothelin-1 and midregional proatrial natriuretic peptide (CT-proET-1 and MR-proANP, respectively vasoconstrictor and vasodilator) on 28-day mortality following septic shock. METHODS: In this observational study which included 99 patients, concentrations of MR-proANP and CT-proET-1 were measured using an immunoluminometric assay three times within the first week after the onset of septic shock. RESULTS: While MR-proANP concentrations were significantly increased in non-survivors in comparison with survivors, no differences were noted for CT-proET-1. Increased MR-proANP concentrations were significantly associated with mortality after both univariate and multivariate analyses, adjusted for usual clinical confounders [SAPS II (simplified acute physiology score II), SOFA (sepsis-related organ failure assessment) scores and number of co-morbidities]. CONCLUSIONS: In septic shock patients, MR-proANP appears to be a good predictor of 28-day mortality, whereas CT-proET-1 does not present any predictive value during monitoring.

Upregulation of the pro-apoptotic genes BID and FAS in septic shock patients.

INTRODUCTION: Lymphocyte apoptosis has been suggested to play a central role in sepsis pathophysiology, and studies in animal models demonstrated that blocking this pathway improves outcome. However, no routine biomarkers of apoptosis are so far available in patients. Thus, the aim of our study was to assess the different biomarkers of apoptosis putatively usable on a routine basis in septic shock. METHODS: Thirteen septic shock patients (sampled twice between days 1 to 2 and days 3 to 5 after diagnosis of shock) and 15 sex-matched and age-matched healthy controls were prospectively enrolled. Apoptosis was measured in lymphocyte subpopulations using flow cytometry (Annexin-V binding, activated caspase-3 and Bcl-2 expressions). Representative pro-apoptotic and anti-apoptotic gene expressions were assessed by quantitative reverse-transcription PCR. Monocyte HLA-DR expression and lymphocyte subpopulation cell counts were measured as markers of sepsis-induced immune dysfunctions. To test for statistical significance, the Mann-Whitney U test was used with correction by the number of tests performed. RESULTS: Flow cytometric measurements of apoptosis in septic shock patients showed an increased Annexin-V binding on CD4+ T cells and an increased active caspase-3 expression on B cells only at days 3 to 5 (sixfold change and twofold change, respectively). Gene expression analysis showed an increased BCL-XL mRNA and an upregulation of the pro-apoptotic genes BID and FAS in septic shock patients (10-fold change and fivefold change, respectively) compared with healthy controls. CONCLUSIONS: The present study highlights the difficulties encountered in monitoring apoptosis on a routine basis in septic patients, whereas in the same sampling conditions and on the same patients, HLA-DR expression and lymphocyte subpopulation cell counts showed characteristics described in the literature. However, pro-apoptotic genes BID and FAS appear to constitute promising apoptosis markers in our hands.

Early assessment of leukocyte alterations at diagnosis of septic shock.

A dramatic decrease in circulating lymphocyte number is regularly described after septic shock. However, it is unknown how early this alteration develops after diagnosis of shock and if it remains stable over time. Twenty-one septic shock patients with no comorbidities were included within 2 h after the beginning of vasopressive treatment. Flow cytometry phenotyping of circulating leukocyte subpopulations and quantitative real-time polymerase chain reaction of T-bet, GATA-3, FOXP3, and RORγ mRNA were performed in patients from the diagnosis of shock and every 6 h during the subsequent 48 h. From their admission in the intensive care unit, patients present with major alterations of circulating leukocyte count (leukocytosis, neutrophilia, and major lymphopenia). The numbers of every lymphocyte subpopulations (T, B, and natural killer cells) were diminished. Gene expression analysis of transcription factors specific for TH1, TH2, CD4CD25 regulatory, and TH17 lymphocytes showed a severe decrease in comparison with healthy individuals' values. These alterations remain stable during the first 48 h after inclusion in the protocol despite early and aggressive resuscitation and antibiotherapy administered in patients. At the time of diagnosis of shock and admission in the intensive care unit, septic patients already present with severe lymphopenia involving every lymphocyte subsets including CD4 T-cell subpopulations. No significant variation could be detected within the first 48 h. This should be taken into account in the forthcoming clinical trials testing immunomodulating therapies in septic shock patients.

Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients.

PURPOSE: Improvements in survival after septic shock will most likely rely on our capacity to manage individualized therapies based on the measurement of rapidly accessible biomarkers. As the early phase of septic shock is dominated by severe alterations of the cardiovascular system, the predictive value for mortality of pro-vasopressin (pro-AVP) and pro-adrenomedullin (pro-ADM), two vasoactive pro-hormones, was assessed. METHODS: In 99 consecutive patients, pro-hormone concentrations were measured (immunoluminometric assay) three times within the first week after the onset of septic shock. RESULTS: Pro-AVP and pro-ADM concentrations were significantly increased in non-survivors in comparison with survivors and were significantly associated with mortality after both univariate and multivariate analysis. Importantly, when assessed as a pair, pro-ADM and pro-AVP were even more informative. CONCLUSIONS: Both Pro-ADM and pro-AVP appear to be good biomarkers for the prediction of 28-day mortality after septic shock. However, their association in a single variable tends to improve their predictive capacity.

Innovative therapeutic strategies for restoring lymphocyte functions in septic patients.

Septic syndromes still remain a major but largely under-recognized healthcare problem worldwide accounting for thousands of deaths every year. Despite numerous clinical trials, therapies have failed to mitigate the devastating effects of these conditions. It is now agreed that the initial hypotheses for sepsis pathophysiology have been misconstrued. Sepsis deeply perturbs immune homeostasis by concomitantly inducing a strong inflammatory response and a major anti-inflammatory process, acting as a negative feedback. Several lines of evidences indicate that this inhibitory response secondly may be deleterious in patients who survived initial resuscitation, as it may be directly responsible for worsening outcome by decreasing resistance to secondary nosocomial infections. In this context, while the majority of clinical and basic science conducted so far has focused on innate immune cell depressed functions (especially monocytes), the contribution of T lymphocyte anergy has been somewhat ignored. This review focuses on lymphocyte dysfunctions described so far in patients and on potential new therapeutic strategies aimed at restoring a functional lymphocytic response after sepsis.