Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy (original) (raw)
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Cancer Immunology, Immunotherapy, 2009
Cancer vaccine trials frequently report on immunological responses, without any clinical beneWt. This paradox may reXect the challenge of discriminating between eVective and pointless immune responses and sparse knowledge on their long-term development. Here, we have analyzed T cell responses in long-term survivors after peptide vaccination. There were three main study aims: (1) to characterize the immune response in patients with a possible clinical beneWt. (2) To analyze the longterm development of responses and eVects of booster vaccination. (3) To investigate whether the Th1/Th2-delineation applies to cancer vaccine responses. T cell clones were generated from all nine patients studied. We Wnd that surviving patients harbor durable tumor-speciWc responses against vaccine antigens from telomerase, RAS or TGF receptor II. Analyses of consecutive samples suggest that booster vaccination is required to induce robust T cell memory. The responses exhibit several features of possible clinical advantage, including combined T-helper and cytotoxic functionality, recognition of naturally processed antigens and diverse HLA-restriction and Wne-speciWcity. CD4 ¡ CD8 ¡ T cell clones display unconventional cytotoxicity and spe-ciWcally kill tumor cells expressing mutated TGF receptor II. Cytokine proWling on the long-term survivors demonstrates high IFN /IL10-ratios, favoring immunity over tolerance, and secretion of multiple chemokines likely to mobilize the innate and adaptive immune system. Interestingly, these pro-inXammatory cytokine proWles do not follow a Th1/Th2-delineation. Most IFN high /IL4 low /IL10 low cultures include high concentrations of hallmark Th2-cytokines IL-5 and IL-13. This does not reXect a mixture of Th1-and Th2-clones, but applies to 19/20 T cell clones conWrmed to be monoclonal through TCR clonotype mapping. The present study identiWes several factors that may promote clinical eYcacy and suggests that cytokine proWling should not rely on the Th1/Th2-paradigm, but assess the overall inXammatory milieu and the balance between key cytokines.
T Cell Memory in Infection, Cancer, and Autoimmunity
Frontiers in Immunology, 2022
Long-term immunological memory represents a unique performance of the adaptive immunity selected during evolution to support long-term survival of species in vertebrates, through protection against dangerous “invaders”, namely, infectious agents or unwanted (e.g., tumor) cells. The balance between the development of T cell memory and various mechanisms of immunoregulation (namely, T cell effector exhaustion and regulatory T cell suppression) dictates the fate in providing protection or not in different conditions, such as (acute or chronic) infection, vaccination, cancer, and autoimmunity. Here, these different environments are taken in consideration to outline the up-to-date cellular and molecular features regulating the development or damping of immunological memory and to delineate therapeutic strategies capable to improve or control it, in order to address pathological contexts, such as infection, tumor, and autoimmunity.
The Potential of Tissue-Resident Memory T Cells for Adoptive Immunotherapy against Cancer
Cells, 2021
Tissue-resident memory T cells (TRM) comprise an important memory T cell subset that mediates local protection upon pathogen re-encounter. TRM populations preferentially localize at entry sites of pathogens, including epithelia of the skin, lungs and intestine, but have also been observed in secondary lymphoid tissue, brain, liver and kidney. More recently, memory T cells characterized as TRM have also been identified in tumors, including but not limited to melanoma, lung carcinoma, cervical carcinoma, gastric carcinoma and ovarian carcinoma. The presence of these memory T cells has been strongly associated with favorable clinical outcomes, which has generated an interest in targeting TRM cells to improve immunotherapy of cancer patients. Nevertheless, intratumoral TRM have also been found to express checkpoint inhibitory receptors, such as PD-1 and LAG-3. Triggering of such inhibitory receptors could induce dysfunction, often referred to as exhaustion, which may limit the effective...
PloS one, 2015
Memory phenotype CD4 T cells are found in normal mice and arise through response to environmental antigens or homeostatic mechanisms. The factors that regulate the homeostasis of memory phenotype CD4 cells are not clear. In the present study we demonstrate that there is a marked accumulation of memory phenotype CD4 cells, specifically of the effector memory (TEM) phenotype, in lymphoid organs and tissues of mice deficient for the negative co-stimulatory receptor programmed death 1 (PD-1). This can be correlated with decreased apoptosis but not with enhanced homeostatic turnover potential of these cells. PD-1 ablation increased the frequency of memory phenotype CD4 IFN-γ producers but decreased the respective frequency of IL-17A-producing cells. In particular, IFN-γ producers were more abundant but IL-17A producing cells were more scarce among PD-1 KO TEM-phenotype cells relative to WT. Transfer of peripheral naïve CD4 T cells suggested that accumulated PD-1 KO TEM-phenotype cells ar...
Memory-like CD8+and CD4+T cells cooperate to break peripheral tolerance under lymphopenic conditions
Proceedings of the National Academy of Sciences, 2008
The onset of autoimmunity in experimental rodent models and patients frequently correlates with a lymphopenic state. In this condition, the immune system has evolved compensatory homeostatic mechanisms that induce quiescent naive T cells to proliferate and differentiate into memory-like lymphocytes even in the apparent absence of antigenic stimulation. Because memory T cells have less stringent requirements for activation than naive cells, we hypothesized that autoreactive T cells that arrive to secondary lymphoid organs in a lymphopenic environment could differentiate and bypass the mechanisms of peripheral tolerance such as those mediated by self-antigen cross-presentation. Here, we show that lymphopenia-driven proliferation and differentiation of potentially autoreactive CD8+T cells into memory-like cells is not sufficient to induce self-reactivity against a pancreatic antigen. Induction of an organ-specific autoimmunity required antigen-specific CD4+T cell help. Notably, we foun...
The Journal of Immunology, 2005
The implantation of small pieces of human primary lung tumor biopsy tissue into SCID mice results in a viable s.c. xenograft in which the tissue architecture, including tumor-associated leukocytes, tumor cells, and stromal cells, is preserved in a functional state. By monitoring changes in tumor volume, gene expression patterns, cell depletion analysis, and the use of function-blocking Abs, we previously established in this xenograft model that exogenous IL-12 mobilizes human tumor-associated leukocytes to kill tumor cells in situ by indirect mechanisms that are dependent upon IFN-␥. In this study immunohistochemistry and FACS characterize the early cellular events in the tumor microenvironment induced by IL-12. By 5 days post-IL-12 treatment, the constitutively present human CD45 ؉ leukocytes have expanded and infiltrated into tumor-rich areas of the xenograft. Two weeks post-treatment, there is expansion of the human leukocytes and complete effacement of the tumor compared with tumor progression and gradual loss of most human leukocytes in control-treated xenografts. Immunohistochemical analyses reveal that the responding human leukocytes are primarily activated or memory T cells, with smaller populations of B cells, macrophages, plasma cells, and plasmacytoid dendritic cells capable of producing IFN-␣. The predominant cell population was also characterized by FACS and was shown to have a phenotype consistent with a CD4 ؉ effector memory T cell. We conclude that quiescent CD4 ؉ effector memory T cells are present within the tumor microenvironment of human lung tumors and can be reactivated by the local and sustained release of IL-12 to proliferate and secrete IFN-␥, leading to tumor cell eradication.
Tumor-specific CD4 + T cells maintain effector and memory tumor-specific CD8 + T cells
European Journal of Immunology, 2014
Immunotherapies that augment anti-tumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4 + T cells enhance CD8 + T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of TRP-1-CD4 + T cells and pmel-CD8 + T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p<0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8 + T cells with tumor-specific cytokine expression. When combined with CD4 + T cells, transfer of total (naïve and effector) or effector CD8 + T cells were highly effective, suggesting CD4 + T cells can help mediate therapeutic effects by maintaining function of activated CD8 + T cells. In addition, CD4 + T cells had a pronounced effect in the early post-transfer period, as their elimination within the first 3-days significantly (p<0.001) reduced therapeutic efficacy. The CD8 + T cells recovered from mice treated with both CD8 + and CD4 + T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4 + T cells help reduce CD8 + Tcell exhaustion. These data support combining immunotherapies that elicit both tumorspecific CD4 + and CD8 + T cells for treatment of patients with cancer.
European Journal of Immunology, 2002
The mechanism of generation of memory cytotoxic T cells (CTL) following immunization remains controversial. Using tumor protection and IFN-+ ELISPOT assays in mice to detect functional CTL, we show that the initial effector CTL burst size after immunization is not directly related to the amount of functional memory CTL formed, suggesting that memory CTL are unlikely to arise stochastically from effector CTL. Induction of MHC class IIrestricted T helper cells at the time of immunization by inclusion of a T helper peptide or protein in the immunogen, is necessary to generate memory CTL, although no T helper cell induction is required to generate effector CTL to a strong MHC class I-binding peptide. Host protective T cell memory correlates with the number of CTL epitope responsive IFN-+secreting memory T cells as measured in an ELISPOT assay at the time of tumor challenge. We conclude that a different antigen presenting environment is required to induce longlasting functional memory CTL, and non-cognate stimulation of the immune system is essential to allow generation of a long-lasting host protective memory CTL response.