CD153 cells and protective immunity against tuberculosis

Submitted by Pierre Lutgen on September 29, 2021 - 14:35 CD4 T cells play a key role in immunity. The paper quoted in the WHO technical document of the use of non-pharmaceutical forms of Artemisia (October 2019) shows that Artemisia annua and Artemisia afra raise CD4 counts and reduce parasitemia of malaria infected patients to 0 on day 11 in 95% of the cases. Tchandema CK, Lutgen P. In vivo trials on the therapeutic effects of encapsulated Artemisia annua and Artemisia afra. Glob J Res Anal. 2016;5(6):228–34. doi:10.15373/2249555X. Not all CD4 T cells recognize Mycobacterium tuberculosis Mtb-infected macrophages, but the frequency of T cells that recognize infected macrophages could correlate with protective immunity. Yash R. Patankar, Rujapak Sutiwisesak, Shayla Boyce Limited recognition of Mycobacterium tuberculosis-infected macrophages by polyclonal CD4 and CD8 T cells from the lungs of infected mice. July 2019 bioRxiv 697805; doi: https://doi.org/10.1101/697805 T cells primed in the lymph nodes during natural infection may not necessarily recognize antigens presented by Mtb-infected macrophages in the lung. Lung CD4 T cells more sensitively recognize Mtb-infected macrophages than lung CD8 T cells. Patankar YR, Sutiwisesak R, Boyce S, Behar SM. Limited recognition of Mycobacterium tuberculosis-infected macrophages by polyclonal CD4 and CD8 T cells from the lungs of infected mice. Mucosal Immunol. 2020 Jan; 13(1):140-148. doi: 10.1038/s41385-019-0217-6. Epub 2019 Oct 21. PMID: 31636345; Mtb specific CD4 T cells in the lung parenchyma express very high levels of multiple activation markers. Lung tissue migratory capacity, rather than IFN-γ production per se, may be a more important property to consider when evaluating antigen-specific CD4 T cell mediated protection against Mtb. The ability of lymphocytes to exit circulation and enter the lung tissue is likely a key feature of their protective capacity during Mtb infection. Mtb-specific T cells are found in both the lung parenchyma and the lung vasculature and can be distinguished via differential expressions of phenotypic markers and very different functional, migratory and host-protective capacities. Sakai S, Mayer-Barber KD, Barber DL. Defining features of protective CD4 T cell responses to Mycobacterium tuberculosis. Curr Opin Immunol. 2014 Aug;29:137-42. doi: 10.1016/j.coi.2014.06.003. PMID: 25000593; PMCID: PMC4122329. The results of a study demonstrate that the CD4 cell count is depressed in approximately one-half of hospitalized HIV-negative patients with tuberculosis and can be as low as that found in HIV-positive patients. A complex array of T cells are implicated in the immune response to TB, but their relative contribution to protection remains undefined. The authors find that we really know little about CD4 cell control in Mtb and suggest that severity of tuberculosis is best judged by standard clinical and radiographic criteria, and that measurement of the CD4 cell count does not provide additional clinically relevant information in HIV-negative patients with tuberculosis. Jones BE, Oo MM, Taikwel EK, Qian D, Kumar A, Maslow ER, Barnes PF. CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis. Clin Infect Dis. 1997 May;24(5):988-91. doi: 10.1093/clinids/24.5.988. PMID: 9142808. Torrado E, Cooper AM (2011) What Do We Really Know about How CD4 T Cells Control Mycobacterium tuberculosis? PLoS Pathog 7(7): e1002196. https://doi.org/10.1371/journal.ppat.1002196 A recent study also shows that specific cells are required. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T cell-mediated protection. However, IFNγ responses do not fully correlate with host protection, and additional antituberculous CD4 T cell effector functions remain unaccounted . The study shows that the superfamily molecule CD153 is required for control of pulmonary Mtb infection. The frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active TB. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection, and CD4 T cells are one important source of this molecule. Sallin MA, Kauffman KD, Riou C, Du Bruyn E, , Wilkinson RJ, Barber DL. Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression. Nat Microbiol. 2018 Nov;3(11):1198-1205. doi: 10.1038/s41564-018-0231-6. Epub 2018 Sep 10. PMID: 30202016. Mice deficient in either CD30 or CD153, or treated with antibodies blocking the effects or CD30 and CD153, and infected with Mycobacterium avium or Mycobacterium bovis BCG exhibit higher bacterial burden, abnormal inflammatory responses with decreased Th1 responses, and this is evidenced by the reduced number of IFN-γ-producing cells.These findings suggest that CD30/CD153 interactions during the anti-mycobacterial immune response are important for the establishment and maintenance of a protective response. Marín ND, García LF. The role of CD30 and CD153 (CD30L) in the anti-mycobacterial immune response. Tuberculosis (Edinb). 2017 Jan;102:8-15. doi: 10.1016/j.tube.2016.10.006. Epub 2016 Nov 1. PMID: 28061955. All this was confirmed by a very recent study : the proportion of CD153 -specific CD4 T cells inversely correlates with Mtb bacterial burden, irrespective of HIV status. The mechanism underlying CD153-induced protection against Mtb is still unknown and further mechanistic studies are required to investigate whether Mtb-specific CD4 T cells expressing CD153 is a cause or a consequence of reduced bacterial burden Du Bruyn, E., Ruzive, S., Lindestam Arlehamn, C.S. et al. Mycobacterium tuberculosis-specific CD4 T cells expressing CD153 inversely associate with bacterial load and disease severity in human tuberculosis. Mucosal Immunol 14, 491–499 (2021). https://doi.org/10.1038/s41385-020-0322-6