The Role of Cytolytic CD8+ T Cells in Suppressing Ongoing HIV Replication in Spontaneous Controller Lymph Nodes
Using TissueGnostics’ tissue cytometry solutions, a recent study revealed important information on how sustained cytolytic CD8+ T cells are central in determining long-term viral control in lymph nodes (LNs). This further elucidates the mechanisms behind the immune control over cancerous diseases, which may be used to develope treatments strategies for more effective results and better patient outcomes.
CD8+ Cell Immune Response
Naïve CD8+ T cells can respond to cancer cells through colossal expansion and differentiation into cytotoxic effector cells, which then travel to LNs throughout the body and fight the disease.1 On arrival at the LNs, CD8+ T cells interact with antigen-presenting cells, which prime these naïve T cells into cytotoxic cells and recirculate them by means of sphingosine-1 phosphate–mediated egress.2 This facilitates the initiation of adaptive immune responses via tight regulation of inter-cellular interactions, triggering a cascade of differentiation to produce enough effectors to fight the disease without clonal exhaustion.1
Follicular CD8+ T cells (fCD8) can detect and irradicate cancerous cells selectively by reacting against tumor-specific antigens. They are also effective in course of antiviral response. Opposed to the majority of circulating CD8+ T cells, fCD8s can access germinal centers (GCs) because they lack CCR7 and express CXCR5. In healthy tissue, fCD8s express low amounts of the cytotoxic effector molecules granzyme B and perforin, which can either support or suppress the immune response.2 However, the mechanisms behind this cell-mediated immune control are not fully understood, and why these effectors molecules suppress or enhance the immune response is not truly known.
CD8+ T Cells and Spontaneous Control of HIV
Some people have spontaneous control of HIV without any medication or antiviral therapy. In such cases, the virus is still present but is suppressed by the CD8+ T cell immune response. These cases allow for a more accurate determination of fCD8’s antiviral role.
Research conducted on peripheral blood (PB) has revealed a correlation between CD8+ T cell-mediated HIV immunity and the level of viremia in individuals.4 Yet, how and how much cytolytic fCD8s regulate immune control over HIV is currently debated as CD8+ cell perforin and granzyme expression in LNs has varied. This indicates that there are undescribed contextual variables likely influencing fCD8 cytotoxicity, which should be determined.
With aims to decipher the mechanisms involved in CD8+ T cell-mediated immunity, a recent study investigated the in situ, ex vivo, and antigen-induced process in LNs and PB samples from spontaneous controllers of HIV that have a variety of ongoing replication of HIV in LNs. Along with this, they examined the compartmentalization of cloned CD8+ T cells, their spatial localization, and their transcriptional variance in LNs and PB in these patients.2
Suppression of HIV Replication by Cytolytic CD8+ T Cells in Spontaneous Controller Lymph Nodes
To uncover the spatial associations between cytolytic CD8+ T cells in spontaneous HIV controllers, the researchers conducted automatic digital imaging analysis of tissue samples by utilizing the tissue cytometry solutions TissueFAXS and StataQuest to investigate three protein biomarkers: CD8, perforin and granzyme B, along with an RNA of HIV using RNAscope. TissueFAXS was used for automatic whole slide imaging of the tissue sections, while StrataQuest App was used for automated nuclear segmentation to identify cell boundaries within follicular GC based on DAPI nuclear staining as well as to quantify marker -positive cells based on the corresponding stainings. The density of perforin and granzyme B co-expressing CD8+ cells was then correlated with the density of cells expressing HIV gagpol RNA across entire LN or within follicular GC.
The study revealed heightened levels of perforin and granzyme B in effector cells specific to the virus, localized near regions of HIV RNA in germinal centers within spontaneous HIV controllers. This finding aligns with prior research suggesting that the immune control of lymphotropic infections is maintained through the recruitment of inflammatory responses, antigen-specific cell proliferation, and the cytotoxic actions of fCD8’s.2
Tissue cytometry results showed CD8+ cells repeatedly appear in clusters alongside elevated perforin and granzyme B expression near HIV RNA+ cells. Quantification of CD8+ cells co-expressing perforin and granzyme B and cells expressing HIV RNA revealed a positive correlation between HIV replication and CD8+ cell cytolytic expression. All in all, their results suggest that fCD8’s express cytotoxic effector molecules in close proximity to active HIV replication sites in situ, maintaining cytolytic control over viral replication within follicles and supporting long-term immunity against the virus. 2
Future studies, however, are still required to help further understand the exact factors that determine T cell compartmentalization and suppression of the immune system, along with any potential associations between CD8+ T cell differentiation, CXCR5 expression, and cytolytic potential.
Conclusion
With TissueGnostics automated imaging solutions and analysis, this study shed important light on how fCD8 cells mediate immune scrutiny against lymphotropic infections and cancers within LN germinal centers. TissueGnostics provides highly adaptable solutions, offering tissue cytometry soltuions that can be shaped for your specific study requirements. If you are interested in how TissueGnostics’ digital imiging and analysis capabilities can assist your research, get in touch, and TissueGnostic’s experts will help to establish and guide your workflow.
References
- Zhang, N. and Bevan, M.J. 2011. CD8+ T cells: foot soldiers of the immune system. Immunity. 35(2), pp.161-168.
- Collins, D.R., Hitschfel, J., Urbach, J.M., Mylvaganam, G.H., Ly, N.L., Arshad, U., Racenet, Z.J., Yanez, A.G., Diefenbach, T.J. and Walker, B.D. 2023. Cytolytic CD8+ T cells infiltrate germinal centers to limit ongoing HIV replication in spontaneous controller lymph nodes. Science immunology. 8(83), p.eade5872.
- Philip, M. and Schietinger, A., 2022. CD8+ T cell differentiation and dysfunction in cancer. Nature Reviews Immunology. 22(4), pp.209-223.
- Collins, D.R., Gaiha, G.D. and Walker, B.D. 2020. CD8+ T cells in HIV control, cure and prevention. Nature Reviews Immunology. 20(8), pp.471-482.
