HLA Mice as a Model to Study T Cell Responses Restricted by Human MHC


HLA Mice as a Model to Study T Cell Responses Restricted by Human MHC

Introduction to HLA and MHC

An HLA (Human Leukocyte Antigen) or human MHC (Major Histocompatibility Complex) is a group of surface protein complexes that presents antigens to downstream immune cells to activate the adaptive immune system against foreign pathogens or injured cells. These molecules are critical for modulating T cell responses and play a major role in several autoimmune diseases including diabetes, arthritis, and multiple sclerosis. The HLA protein family is one of the most polymorphic gene families within the human genome. For classification purposes, researchers divide these complexes into two main groups, each with different characteristics: HLA class I and HLA class II (Table 1).


 HLA Class IHLA Class II

Alleles

A, B, CDP, DQ, DR

Location

All nucleated cellsAntigen-presenting cells (APCs)

Structure

Single chain consisting of α1, α2, α3 domains, coupled with B2mHeterologous chain consisting of α1, β1, and α2, β2

Antigen

EndogenousExogenous

T cells Activated

CD8+ cellsCD4+ cells
Table 1: Summary of differences between HLA Class I and Class II Complexes.

Taconic's Chimeric HLA Mice Allow Identification of HLA-Restricted Epitopes

MHC molecules found in mice do not necessarily present the same antigens as HLA molecules. Therefore, in order to enable the study of HLA epitopes, HLA transgenic mice were generated1-4. These models have allowed researchers to study HLA-restricted T cell responses in vivo for infectious disease, vaccine, and autoimmune research. Mice expressing full-length HLA showed some initial promise in the identification of HLA-restricted responses following immunization with viral antigens5. Nevertheless, these mice suffered from inefficient HLA-restricted T cell responses, which is believed to be a result of HLA not being recognized effectively by murine T cell receptors (TCRs)6.

To increase the efficiency of HLA recognition by murine T cells, Taconic Biosciences provides chimeric HLA mice with a humanized antigen-binding domain coupled with murine MHC domains that activate downstream mouse T cells (Table 2). This ensures that the specificity of HLA-restricted epitope presentation is not compromised in chimeric HLA-expressing cells while still allowing for efficient downstream activation of CD4 or CD8 T cells (Figure 1).

Figure 1: Taconic's HLA mice express human (grey) HLA domains to ensure HLA-restricted antigen presentation while murine MHC (cyan) domains result in efficient binding to murine CD8/4 and subsequent downstream T cell activation.
Figure 1: Taconic's HLA mice express human (grey) HLA domains to ensure HLA-restricted antigen presentation while murine MHC (cyan) domains result in efficient binding to murine CD8/4 and subsequent downstream T cell activation.

Understanding the Relationship Between Murine MHC Expression and HLA Restriction in Taconic's HLA models

Taconic's class I HLA mice were originally obtained from scientists at Pharmexa-Epimmune. These strains are offered on a CB6F1 strain background, generated by crossing homozygous HLA C57BL/6 with wild type BALB/cAnNTac mice. Mice on an F1 background may have a better HLA-restricted immune response than mice on a pure B6 background. It has been shown that loss of murine MHC leads to reduction in T cell diversity and population numbers7,8. Thus, presence of BALB/c and C57BL/6 murine H2 in CB6F1 offspring may help maintain a sufficiently large and diverse naïve T cell population in comparison to HLA mice of a pure B6 background and in comparison to other transgenic class I HLA models on a murine MHC knockout background which may have reduced T cell numbers and diversity. CB6F1 mice display hybrid vigor and display fewer health issues compared to inbred parental strains since they are heterozygous for all autosomal loci that differ between C57BL/6 and BALB/c genomes and thus lack many of the inherent idiosyncrasies of either parental line. Depending on your study requirements, Taconic can also provide class I HLA transgenic mice on pure B6 backgrounds (quantities may be limited). Consultation with experienced PhD-level scientists is recommended before ordering these animals on a pure background.

In contrast to HLA class I mice, Taconic's HLA class II HLA-DR4 mice do not express murine MHC, which is believed to improve the utilization of HLA-DR4 as a restricting element. The absence of murine class II MHC seems necessary to elicit sufficient HLA-class II restricted response9, while the lack of murine MHC is not necessary for proper function of class I HLA mice. Hence, HLA-DR4 animals are provided on a pure B6 background. Despite these differences in strain backgrounds between the class I and class II transgenic mice, both groups still show HLA-restricted response to a variety of infections10-13.

HLA CLASS I
MODEL STRAIN BACKGROUND NOMENCLATURE DESCRIPTION MGI
HLA-A2.1 C57BL/6 or CB6F1 CB6F1-Tg(HLA-A*0201/H2-Kb)A*0201 Expresses the chimeric HLA-A2.1 class I molecule (representing the HLA-A2 supertype) on the surface of T and B cells. Inquire for C57BL/6 version. Link
HLA-A11 C57BL/6 or CB6F1 CB6F1-Tg(HLA-A*1101/H2-Kb)A11.01 Expresses the chimeric HLA-A11 class I molecule (representing the HLA-A3 supertype) on the surface of T and B cells. Inquire for C57BL/6 version. Link
HLA-A1 C57BL/6 or CB6F1 CB6F1-Tg(HLA-A*0101/H2-Kb)A1.01 Expresses the chimeric HLA-A1 class I molecule (representing the HLA-A1 supertype) on the surface of T and B cells. Inquire for C57BL/6 version. Link
HLA-A24 C57BL/6 or CB6F1 CB6F1-Tg(HLA-A*2402/H2-Kb)A24.01 Expresses the chimeric HLA-A24 class I molecule (representing the HLA-A24 supertype) on the surface of T and B cells. Inquire for C57BL/6 version. Link
HLA-B7 C57BL/6 or CB6F1 CB6F1-B2mtm1Unc Tg(B2M)55Hpl Tg(HLA-B*0702/H2-Kb)B7.xx Expresses the chimeric HLA-B7 class I molecule (representing the HLA-B7 supertype) on the surface of T and B cells. Inquire for C57BL/6 version. Link
HLA-B44 C57BL/6 or CB6F1 CB6F1-Tg(HLA-B*4002/H2-Kb)B44.01 Expresses the chimeric HLA-B44 class I molecule (representing the HLA-B44 supertype) on the surface of T and B cells. Inquire for C57BL/6 version. Link
HLA CLASS II
Abb Knockout/ Transgenic HLA-DR4 C57BL/6 B6.129S2-H2-Ab1tm1Gru Tg(HLA-DRA/H2-Ea,HLA-DRB1*0401/H2-Eb)1Kito Expresses the chimeric HLA-DR4 class II molecule on the surface of T and B cells. Link
Table 2: Summary of different HLA mice available exclusively from Taconic.

Not All HLA Mice Perform the Same

It is important to note that not all HLA-related mouse models perform the same when it comes to HLA restriction. HLA mice can differ based on:

  1. Chimeric or fully-humanized HLA
  2. HLA gene copy number
  3. HLA transgene insertion sites
  4. Mouse MHC expressed or knocked out
  5. Background strain differences
These different factors can significantly impact antigen presentation and immunodominance, affecting the outcome of your studies. Thus, it is important to take into consideration the differences between different HLA mice strains when using these mice.

Taconic's HLA mice have been used to study human class I- or class II-restricted T cells in autoimmune diseases, infectious diseases, and vaccine development. As valuable tools in evaluating human HLA restricted T cell-mediated vaccine efficacy in oncology, they also offer researchers greater translatability in studying immune responses.

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References:
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2. Ito K, Bian HJ, Molina M, Han J, Magram J, Saar E, Belunis C, Bolin DR, Arceo R, Campbell R, Falcioni F, Vidović D, Hammer J, Nagy ZA. HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis. J Exp Med. 1996 Jun 1;183(6):2635-44. doi: 10.1084/jem.183.6.2635. PMID: 8676084; PMCID: PMC2192625.
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4. Hill JA, Bell DA, Brintnell W, Yue D, Wehrli B, Jevnikar AM, Lee DM, Hueber W, Robinson WH, Cairns E. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J Exp Med. 2008 Apr 14;205(4):967-79. doi: 10.1084/jem.20072051. Epub 2008 Apr 7. PMID: 18391064; PMCID: PMC2292232.
5. Kievits F, Ivanyi P, Krimpenfort P, Berns A, Ploegh HL. HLA-restricted recognition of viral antigens in HLA transgenic mice. Nature. 1987 Oct 1-7;329(6138):447-9. doi: 10.1038/329447a0. PMID: 2821399.
6. Le AX, Bernhard EJ, Holterman MJ, Strub S, Parham P, Lacy E, Engelhard VH. Cytotoxic T cell responses in HLA-A2.1 transgenic mice. Recognition of HLA alloantigens and utilization of HLA-A2.1 as a restriction element. J Immunol. 1989 Feb 15;142(4):1366-71. PMID: 2464645.
7. Grusby MJ, Johnson RS, Papaioannou VE, Glimcher LH. (1991) Depletion of CD4+ T-Cells in Major Histocompatibility Complex Class II — Deficient Mice. Science, 253(5026):1417-1420.
8. Chitilian HV, Auchincloss H Jr. Studies of transplantation immunology with major histocompatibility complex knockout mice. J Heart Lung Transplant. 1997 Feb;16(2):153-9. PMID: 9059926.
9. Pajot A, Pancré V, Fazilleau N, Michel ML, Angyalosi G, Ojcius DM, Auriault C, Lemonnier FA, Lone YC. Comparison of HLA-DR1-restricted T cell response induced in HLA-DR1 transgenic mice deficient for murine MHC class II and HLA-DR1 transgenic mice expressing endogenous murine MHC class II molecules. Int Immunol. 2004 Sep;16(9):1275-82. PMID: 15249541.
10. DiPiazza A, Richards K, Poulton N, Sant AJ. Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity. Clin Vaccine Immunol. 2017 Mar 6;24(3):e00548-16. doi: 10.1128/CVI.00548-16. PMID: 28100497; PMCID: PMC5339641.
11. Musson JA, Reynolds CJ, Rinchai D, Nithichanon A, Khaenam P, Favry E, Spink N, Chu KK, De Soyza A, Bancroft GJ, Lertmemongkolchai G, Maillere B, Boyton RJ, Altmann DM, Robinson JH. CD4+ T cell epitopes of FliC conserved between strains of Burkholderia: implications for vaccines against melioidosis and cepacia complex in cystic fibrosis. J Immunol. 2014 Dec 15;193(12):6041-9. doi: 10.4049/jimmunol.1402273. Epub 2014 Nov 12. PMID: 25392525; PMCID: PMC4258416.
12. Yang J, James E, Roti M, Huston L, Gebe JA, Kwok WW. Searching immunodominant epitopes prior to epidemic: HLA class II-restricted SARS-CoV spike protein epitopes in unexposed individuals. Int Immunol. 2009 Jan;21(1):63-71. doi: 10.1093/intimm/dxn124. Epub 2008 Dec 2. PMID: 19050106; PMCID: PMC2638843.
13. Greidinger EL, Zang YJ, Jaimes K, Martinez L, Nassiri M, Hoffman RW. CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-transgenic murine model of mixed connective tissue disease. J Immunol. 2008 Jun 15;180(12):8444-54. doi: 10.4049/jimmunol.180.12.8444. PMID: 18523312; PMCID: PMC2919051.
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