Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells

Abstract Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 has been shown to enhance anti-tumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. Here we established a vaccination protocol that combines selective engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4-blockade. We found that vaccination together with RIG-I ligation strongly synergized with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8+ T cells and potent anti-tumor immunity. Cross-priming of cytotoxic T cells as well as anti-tumor immunity required the adapter protein MAVS and type I interferon (IFN) signaling and were mediated by dendritic cells. In addition, the benefit of the combined immunization with anti-CTLA-4 was reduced by systemic antibiotics pointing to the requisite of an intact commensal microbiota in this context. Together, our findings describe a novel combinatorial strategy that may form the basis for the design of new type I IFN-based regimens that enhance antigen-specific T cell reactivity against cancer. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Enhanced Susceptibility of Galectin-1 Deficient Mice to Experimental Colitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.687443 ◽

2021 ◽

Vol 12 ◽

Author(s):

Raquel Fernandez-Perez ◽

Mercedes Lopez-Santalla ◽

Rebeca Sánchez-Domínguez ◽

Omaira Alberquilla ◽

Irene Gutiérrez-Cañas ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Inflammatory Response ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Cell Trafficking ◽

Wild Type ◽

Cell Reactivity ◽

Deficient Mice

Galectin-1 is a β-galactoside-binding lectin, ubiquitously expressed in stromal, epithelial, and different subsets of immune cells. Galectin-1 is the prototype member of the galectin family which shares specificity with β-galactoside containing proteins and lipids. Immunomodulatory functions have been ascribed to endogenous galectin-1 due to its induction of T cell apoptosis, inhibitory effects of neutrophils and T cell trafficking. Several studies have demonstrated that administration of recombinant galectin-1 suppressed experimental colitis by modulating adaptive immune responses altering the fate and phenotype of T cells. However, the role of endogenous galectin-1 in intestinal inflammation is poorly defined. In the present study, the well-characterized acute dextran sulfate sodium (DSS)-induced model of ulcerative colitis was used to study the function of endogenous galectin-1 during the development of intestinal inflammation. We found that galectin-1 deficient mice (Lgals1−/− mice) displayed a more severe intestinal inflammation, characterized by significantly elevated clinical scores, than their wild type counterparts. The mechanisms underlying the enhanced inflammatory response in colitic Lgals1−/− mice involved an altered Th17/Th1 profile of effector CD4+ T cells. Furthermore, increased frequencies of Foxp3+CD4+ regulatory T cells in colon lamina propria in Lgals1−/− mice were found. Strikingly, the exacerbated intestinal inflammatory response observed in Lgals1−/− mice was alleviated by adoptive transfer of wild type Foxp3+CD4+ regulatory T cells at induction of colitis. Altogether, these data highlight the importance of endogenous galectin-1 as a novel determinant in regulating T cell reactivity during the development of intestinal inflammation.

Download Full-text

Impact of pre-existing T cell immunity to SARS-CoV-2 in uninfected individuals with COVID-19 mortality in different countries

10.1101/2020.10.03.20206151 ◽

2020 ◽

Author(s):

Gennadi V. Glinsky

Keyword(s):

T Cells ◽

T Cell ◽

Herd Immunity ◽

Inverse Correlation ◽

Mortality Rates ◽

Virus Spread ◽

Cell Reactivity ◽

Cell Immunity ◽

Potential Impact ◽

T Cell Reactivity

AbstractSeveral recent studies identified SARS-CoV-2 reactive T cells in people without exposure to the virus. However, pathophysiological implications of these findings remain unknown. Here, the potential impact of pre-existing T cell reactivity against SARS-CoV-2 in uninfected individuals on markedly different COVID-19 mortality levels in different countries has been investigated. The inverse correlation is documented between the prevalence of pre-existing SARS-CoV-2 reactive T cells in people without exposure to the virus and COVID-19 mortality rates in different countries. In countries with similar levels of pre-existing SARS-CoV-2 cross-reactive T cells in uninfected individuals, differences in COVID-19 mortality appear linked with the extend and consistency of implementations of social measures designed to limit the transmission of SARS-CoV-2 (lockdown; physical distancing; mask wearing). Collectively, these observations support the model that the level of pre-existing SARS-CoV-2 reactive T cells is one of the important determinants of the innate herd immunity against COVID-19. Together with the consistent social measures directed to limit the virus spread, high levels of pre-existing SARS-CoV-2 reactive T cells appear significant determinants diminishing the COVID-19 mortality. Observations reported in this contribution should have significant impact on definitions of the herd immunity threshold required to effectively stop the pandemic in different countries across the globe.

Download Full-text

Functional Comparison of Freshly Isolated and Ex-Vivo Expanded CD4+CD25+Foxp3+ Regulatory T Cells in Suppressing Murine Acute GvHD

Blood ◽

10.1182/blood.v112.11.812.812 ◽

2008 ◽

Vol 112 (11) ◽

pp. 812-812 ◽

Cited By ~ 1

Author(s):

Emanuela I Sega ◽

Dennis Leveson-Gower ◽

Vu H. Nguyen ◽

Robert Negrin

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Acute Gvhd ◽

Bone Marrow Cells ◽

Ex Vivo ◽

Allogeneic Bone ◽

Cell Reactivity ◽

Hematopoietic Stem

Abstract Graft versus host disease (GVHD) is a major complication of hematopoietic stem cell transplantation resulting from donor T cell reactivity against host tissue antigens. CD4+CD25+Foxp3+ regulatory T cells (Treg) are known to be important in maintaining self tolerance and preventing autoimmunity. Using murine models of acute GVHD in which allogeneic bone marrow cells are transplanted into lethally irradiated hosts, we and others have shown that donor Treg are able to suppress GVHD induced by donor allogeneic T cells and dramatically improve survival. Treg are rare and suppression of GVHD requires adequate numbers of Treg in relation to the number of conventional T cells (Tcon). To overcome this problem, expansion of Treg has been performed, however there has not been a head to head comparison of the function of expanded vs fresh Treg. Highly purified CD4+CD25+Foxp3+ T cells (>98% purity) were expanded using anti-CD3/anti-CD28 dynabeads and 1000 U/ml IL-2. Under these conditions, after five days Treg expanded up to 13 fold while maintaining high Foxp3 expression levels (85–90%). Longer expansion periods result in more T cell expansion but an overgrowth of Foxp3 negative T cells. In a mixed lymphocyte reaction assay, the ex-vivo expanded Treg efficiently suppressed the proliferation of alloreactive T cells. The expanded Treg were evaluated in an in vivo acute GVHD mouse model in direct comparison with freshly isolated Treg using a novel bioluminescent imaging assay that allowed for assessment of Tcon proliferation in addition to traditional metrics of GVHD severity including weight gain, survival and GVHD score. Initial experiments show that, similar to freshly isolated Treg, the ex-vivo expanded Treg suppress GVHD symptoms and improve survival, although a greater number of expanded Treg were required comparable to freshly isolated Treg. The mean GVHD score for the Tcon alone group was 5.8±1.02. Fresh Treg added at 1:1 ratio decreased the GVHD score to 0.75±0.25 (p=0.0036). Ex-vivo expanded Treg demonstrated a dose-dependent decrease in GVHD score, although four times more expanded Treg were needed to obtain a similar reduction in GVHD score (0.50±0.5, p=0.0036). This observed difference in potency was not due to the ex-vivo expanded Treg being short-lived when infused in mice. Bioluminescence imaging of luciferase positive (luc+) cultured Treg showed the same in vivo persistence as freshly isolated Treg. The ability to expand ex-vivo generated Treg is greater than the difference in potency, making ex-vivo expanded Treg potentially a viable option for treatment of GVHD, however, increased ratios of Treg:Tcon are likely to be required.

Download Full-text

Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20050732 ◽

2005 ◽

Vol 202 (7) ◽

pp. 907-912 ◽

Cited By ~ 667

Author(s):

Luca Gattinoni ◽

Steven E. Finkelstein ◽

Christopher A. Klebanoff ◽

Paul A. Antony ◽

Douglas C. Palmer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Adoptive Cell Transfer ◽

Peripheral Tolerance ◽

Antitumor Efficacy ◽

Cell Reactivity ◽

T Cell Reactivity ◽

Homeostatic Cytokines ◽

Cell Functionality

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γC cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

Download Full-text

Interaction between T cells and murine acquired immunodeficiency virus superantigen: effect of second signal on T cell reactivity to the MAIDS virus superantigen

International Immunology ◽

10.1093/intimm/5.6.583 ◽

1993 ◽

Vol 5 (6) ◽

pp. 583-590 ◽

Cited By ~ 4

Author(s):

Mark Heise ◽

Kevin Chow ◽

Osami Kanagawa

Keyword(s):

T Cells ◽

T Cell ◽

Cell Reactivity ◽

Immunodeficiency Virus ◽

Acquired Immunodeficiency ◽

T Cell Reactivity

Download Full-text

T-Cell Reactivity against Streptococcal Antigens in the Periphery Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic Heart Disease Patients

Infection and Immunity ◽

10.1128/iai.69.9.5345-5351.2001 ◽

2001 ◽

Vol 69 (9) ◽

pp. 5345-5351 ◽

Cited By ~ 64

Author(s):

Luiza Guilherme ◽

Sandra E. Oshiro ◽

Kellen C. Faé ◽

Edécio Cunha-Neto ◽

Guilherme Renesto ◽

...

Keyword(s):

T Cells ◽

Heart Disease ◽

T Cell ◽

Rheumatic Heart Disease ◽

Peripheral Blood ◽

Cell Reactivity ◽

T Cell Clones ◽

Cell Clones ◽

T Cell Reactivity ◽

Rheumatic Heart

ABSTRACT T-cell molecular mimicry between streptococcal and heart proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease (RHD). We searched for immunodominant T-cell M5 epitopes among RHD patients with defined clinical outcomes and compared the T-cell reactivities of peripheral blood and intralesional T cells from patients with severe RHD. The role of HLA class II molecules in the presentation of M5 peptides was also evaluated. We studied the T-cell reactivity against M5 peptides and heart proteins on peripheral blood mononuclear cells (PBMC) from 74 RHD patients grouped according to the severity of disease, along with intralesional and peripheral T-cell clones from RHD patients. Peptides encompassing residues 1 to 25, 81 to 103, 125 to 139, and 163 to 177 were more frequently recognized by PBMC from RHD patients than by those from controls. The M5 peptide encompassing residues 81 to 96 [M5(81–96) peptide] was most frequently recognized by PBMC from HLA-DR7+DR53+ patients with severe RHD, and 46.9% (15 of 32) and 43% (3 of 7) of heart-infiltrating and PBMC-derived peptide-reactive T-cell clones, respectively, recognized the M5(81–103) region. Heart proteins were recognized more frequently by PBMC from patients with severe RHD than by those from patients with mild RHD. The similar pattern of T-cell reactivity found with both peripheral blood and heart-infiltrating T cells is consistent with the migration of M-protein-sensitized T cells to the heart tissue. Conversely, the presence of heart-reactive T cells in the PBMC of patients with severe RHD also suggests a spillover of sensitized T cells from the heart lesion.

Download Full-text