HLA class II-Restricted CD8+ T cells in HIV-1 Virus Controllers

Nyanhete, Tinashe; Frisbee, Alyse; Bradley, Todd; Faison, William J.; Robins, Elizabeth; Payne, Tamika L.; Freel, Stephanie A.; Weinhold, Kent J.; Wiehe, Kevin; Haynes, Barton F.; Ferrari, Guido; Li, Qi-Jing; Moody, M. Anthony; Tomaras, Georgia D.

doi:10.1038/s41598-019-46462-8

Cited by 7 publications

(5 citation statements)

References 89 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A question that arises from our results is how TCR specificity impacts on CD4-derived CD8 T cells. Antigen-restricted MHC class II-specific CD8 + T cells have been described in HIVinfected patients (38)(39)(40). Moreover, a recent study reports the in vivo generation of a CD4−CD8ab + MHC II-recognizing lineage from effector CD4 + T cells using murine models of acute infection (41).…”

Section: Discussionmentioning

confidence: 99%

Human CD4 T Cells From Thymus and Cord Blood Are Convertible Into CD8 T Cells by IL-4

et al. 2022

View full text Add to dashboard Cite

Commitment to the CD4+ or CD8+ T cell lineages is linked to the acquisition of a functional program broadly defined by helper and cytotoxic properties, respectively. The mechanisms underlying these processes in the human thymus remain largely unclear. Moreover, recent thymic emigrants are thought to have some degree of plasticity, which may be important for the shaping of the immune system and adjustment to specific peripheral needs. We show here that IL-4 induces proliferation-independent de novo synthesis of CD8αβ in human CD4 single-positive (SP) thymocytes, generating a stable CD8SP population that features a diverse TCRαβ repertoire, CD4 expression shut-down and ThPOK downregulation. IL-4 also promotes an innate-like program in both CD4SP and CD8SP thymocytes, characterized by Eomes upregulation in the absence of T-bet, in line with its recognized role in the generation of thymic innate-like CD8+ T cells. The clinical relevance of these findings is further supported by the profile of IL-4 production and IL-4 receptor expression that we identified in the human thymus. Importantly, human cord blood CD4+ T cells preserve the ability to generate Eomes+ CD8+ T cells in the presence of IL-4, with implications in neonatal immunity. Our results support a role for IL-4 in the dynamic regulation of human thymocyte plasticity and identify novel strategies to modulate immune responses.

show abstract

Section: Discussionmentioning

confidence: 99%

Human CD4 T Cells From Thymus and Cord Blood Are Convertible Into CD8 T Cells by IL-4

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Reports of T cells with αβ TCRs that violate the norms of MHC class restriction date back at least 40 years 15,16 . Class-mismatched T cells or TCRs have since been described in the context of viruses, cancer, autoimmunity, and transplantation [17][18][19][20][21][22][23][24][25][26][27] . Although seemingly rare, they Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the hallmark of MHC class restriction, reports of CD4 + T cells that recognize antigens presented by class I instead of class II MHC proteins, and vice versa, date back nearly 40 years 15,16 . Such "class-mismatched" T cells and TCRs have since been described in the context of viruses, cancer, autoimmunity, and transplantation [17][18][19][20][21][22][23][24][25][26][27] . However, few studies have characterized the molecular properties of mismatched TCRs and the extent to which they follow other paradigms of TCR molecular recognition.…”

mentioning

confidence: 99%

A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry

et al. 2022

View full text Add to dashboard Cite

MHC restriction, which describes the binding of TCRs from CD4+ T cells to class II MHC proteins and TCRs from CD8+ T cells to class I MHC proteins, is a hallmark of immunology. Seemingly rare TCRs that break this paradigm exist, but mechanistic insight into their behavior is lacking. TIL1383I is a prototypical class-mismatched TCR, cloned from a CD4+ T cell but recognizing the tyrosinase tumor antigen presented by the class I MHC HLA-A2 in a fully functional manner. Here we find that TIL1383I binds this class I target with a highly atypical geometry. Despite unorthodox binding, TCR signaling, antigen specificity, and the ability to use CD8 are maintained. Structurally, a key feature of TIL1383I is an exceptionally long CDR3β loop that mediates functions that are traditionally performed separately by hypervariable and germline loops in canonical TCR structures. Our findings thus expand the range of known TCR binding geometries compatible with normal function and specificity, provide insight into the determinants of MHC restriction, and may help guide TCR selection and engineering for immunotherapy.

show abstract

“…It is also not clear if humans can generate unconventional immune responses reported in animal studies. A study of HIV elite controllers showed that HLA-II restricted CD8 + T cell responses exist in humans but are very rare (178), and highly unlikely to be elicited by vaccination. On the other hand, recent studies showed that HLA-E restricted responses are much more common in humans than previously appreciated, which opens up the possibility of inducing such responses by vaccination (179).…”

Section: Cmv-based Vector Vaccinesmentioning

confidence: 99%

Major Scientific Hurdles in HIV Vaccine Development: Historical Perspective and Future Directions

2020

View full text Add to dashboard Cite

Following the discovery of HIV as a causative agent of AIDS, the expectation was to rapidly develop a vaccine; but thirty years later, we still do not have a licensed vaccine. Progress has been hindered by the extensive genetic variability of HIV and our limited understanding of immune responses required to protect against HIV acquisition. Nonetheless, valuable knowledge accrued from numerous basic and translational science research studies and vaccine trials has provided insight into the structural biology of the virus, immunogen design and novel vaccine delivery systems that will likely constitute an effective vaccine. Furthermore, stakeholders now appreciate the daunting scientific challenges of developing an effective HIV vaccine, hence the increased advocacy for collaborative efforts among academic research scientists, governments, pharmaceutical industry, philanthropy, and regulatory entities. In this review, we highlight the history of HIV vaccine development efforts, highlighting major challenges and future directions.

show abstract

HLA class II-Restricted CD8+ T cells in HIV-1 Virus Controllers

Cited by 7 publications

References 89 publications

Human CD4 T Cells From Thymus and Cord Blood Are Convertible Into CD8 T Cells by IL-4

Human CD4 T Cells From Thymus and Cord Blood Are Convertible Into CD8 T Cells by IL-4

A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry

Major Scientific Hurdles in HIV Vaccine Development: Historical Perspective and Future Directions

Contact Info

Product

Resources

About